RRM2

Summary

RRM2 (ribonucleotide reductase regulatory subunit M2, HGNC:10452) is a protein-coding gene on chromosome 2p25.1, encoding Ribonucleoside-diphosphate reductase subunit M2 (P31350). Provides the precursors necessary for DNA synthesis. In precision oncology, RRM2 OVEREXPRESSION is associated with resistance to Gemcitabine in Pancreatic Cancer (CIViC Level D). It is a common-essential gene (DepMap: required in 99.8% of cancer cell lines).

This gene encodes one of two non-identical subunits for ribonucleotide reductase. This reductase catalyzes the formation of deoxyribonucleotides from ribonucleotides. Synthesis of the encoded protein (M2) is regulated in a cell-cycle dependent fashion. Transcription from this gene can initiate from alternative promoters, which results in two isoforms that differ in the lengths of their N-termini. Related pseudogenes have been identified on chromosomes 1 and X.

Source: NCBI Gene 6241 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 38 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Cancer dependency (DepMap): dependent in 99.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_001034

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10452
Approved symbol	RRM2
Name	ribonucleotide reductase regulatory subunit M2
Location	2p25.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ25102
Ensembl gene	ENSG00000171848
Ensembl biotype	protein_coding
OMIM	180390
Entrez	6241

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 10 protein_coding, 8 retained_intron, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000304567, ENST00000360566, ENST00000381786, ENST00000459969, ENST00000461327, ENST00000462343, ENST00000485717, ENST00000487591, ENST00000491447, ENST00000498343, ENST00000607140, ENST00000615152, ENST00000641198, ENST00000641498, ENST00000642996, ENST00000646978, ENST00000652660, ENST00000869144, ENST00000931747, ENST00000931748, ENST00000931749, ENST00000931750, ENST00000931751

RefSeq mRNA: 2 — MANE Select: NM_001034 NM_001034, NM_001165931

CCDS: CCDS1669, CCDS54334

Canonical transcript exons

ENST00000304567 — 10 exons

Exon	Start	End
ENSE00001168551	10126875	10126969
ENSE00003086028	10124717	10124850
ENSE00003814275	10122739	10122897
ENSE00003841901	10123387	10123530
ENSE00003843841	10127087	10127220
ENSE00003844776	10128848	10128952
ENSE00003845664	10129041	10129154
ENSE00003846042	10122983	10123057
ENSE00003848919	10129234	10131414
ENSE00003850689	10123736	10123852

Expression profiles

Bgee: expression breadth ubiquitous, 233 present calls, max score 99.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 135.6397 / max 2017.8616, expressed in 1645 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
18812	131.9746	1636
18810	1.5474	729
18809	0.6118	356
18814	0.4031	176
18811	0.2969	169
18813	0.2859	151
18815	0.2587	136
18816	0.1417	61
18817	0.1195	38

Top tissues by expression

283 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.70	gold quality
oocyte	CL:0000023	99.20	gold quality
ventricular zone	UBERON:0003053	97.65	gold quality
ganglionic eminence	UBERON:0004023	97.32	gold quality
embryo	UBERON:0000922	97.29	gold quality
esophagus squamous epithelium	UBERON:0006920	97.07	gold quality
trabecular bone tissue	UBERON:0002483	96.59	gold quality
thymus	UBERON:0002370	96.21	gold quality
bone marrow	UBERON:0002371	96.14	gold quality
squamous epithelium	UBERON:0006914	95.83	gold quality
cervix squamous epithelium	UBERON:0006922	95.73	gold quality
bone marrow cell	CL:0002092	95.01	gold quality
epithelium of esophagus	UBERON:0001976	94.73	gold quality
tongue squamous epithelium	UBERON:0006919	93.87	gold quality
amniotic fluid	UBERON:0000173	93.57	gold quality
gingival epithelium	UBERON:0001949	93.38	gold quality
vermiform appendix	UBERON:0001154	93.34	gold quality
mucosa of transverse colon	UBERON:0004991	91.98	gold quality
rectum	UBERON:0001052	91.75	gold quality
stromal cell of endometrium	CL:0002255	91.31	gold quality
gingiva	UBERON:0001828	91.31	gold quality
tibia	UBERON:0000979	91.27	gold quality
ileal mucosa	UBERON:0000331	91.26	gold quality
oral cavity	UBERON:0000167	91.16	gold quality
caecum	UBERON:0001153	90.61	gold quality
epithelium of nasopharynx	UBERON:0001951	89.22	gold quality
mucosa of sigmoid colon	UBERON:0004993	88.83	gold quality
colonic mucosa	UBERON:0000317	88.64	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.56	gold quality
esophagus mucosa	UBERON:0002469	88.47	gold quality

Single-cell (SCXA)

Detected in 30 experiment(s), a significant marker in 26.

Experiment	Marker?	Max mean expression
E-GEOD-81383	yes	1535.87
E-GEOD-99795	yes	1109.40
E-MTAB-7052	yes	691.69
E-CURD-120	yes	651.82
E-MTAB-8894	yes	585.64
E-HCAD-5	yes	582.81
E-MTAB-10042	yes	481.90
E-CURD-77	yes	467.73
E-MTAB-6678	yes	453.61
E-MTAB-9467	yes	429.10
E-HCAD-32	yes	405.72
E-MTAB-10485	yes	389.16
E-HCAD-1	yes	354.90
E-MTAB-10290	yes	320.68
E-MTAB-11121	yes	278.14

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, E2F1, E2F4, NFKB, POU2F1, SP1, SRSF1, SRSF2, TFAP2A

miRNA regulators (miRDB)

118 targeting RRM2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-3658	99.96	73.87	4379
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-381-3P	99.93	71.87	2854

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• Human ribonucleotide reductase M2 subunit gene amplification and transcriptional regulation in a homogeneous staining chromosome region responsible for the mechanism of drug resistance (PMID:11978967)
• Characterization of the human ribonucleotide reductase M2 subunit gene; genomic structure and promoter analyses (PMID:11978970)
• Wild-type p53 regulates human ribonucleotide reductase by protein-protein interaction with p53R2 as well as hRRM2 subunits. (PMID:12615712)
• Sequences downstream of the transcription initiation site are important for proper initiation and regulation of this gene’s transcription. (PMID:12694192)
• Expression of antisense hRRM2 in PC3 cells led to decreased hRRM2 expression and resulted in greater sensitivity to UV than observed in wild-type PC3 cells. (PMID:14583450)
• Susceptibility differences to RR inhibitors between hRRM1 and hRRM2 may lead to a new direction in drug design for human cancer treatment. (PMID:14729598)
• R2 subunitof RNR can substuitute for the function of p53R2 in providing dNTPs for DNA repair in cells lacking functional p53R2. (PMID:15096505)
• RRM2 and p53R2 subunits share the same binding site on RRM1 (PMID:16376858)
• NF-kappaB is a key mediator of the invasive phenotypic changes induced by RRM2 overexpression. (PMID:17222798)
• RR M2 protein may not have a critical role in the malignant potential of pancreatic cancer (PMID:18278438)
• Ribonucleotide reductase subunit RRM2 mRNA expression in lung adenocarcinoma is associated with clinical outcome of docetaxel/gemcitabine therapy. (PMID:18414411)
• Esophageal and gastric cancers overexpressed RRM2 protein when compared to prostate cancer. Esophageal and gastric cancers also overexpressed RRM2 mRNA when compared to prostate cancer (PMID:18941749)
• RRM2 mRNA levels were assessed by quantitative PCR and correlated with response, time to progression and survival (PMID:19002265)
• The redox property, structure, and function of hRRM2 and p53R2, are studied. (PMID:19082948)
• These findings suggest a positive role of RRM2 in tumor angiogenesis and growth through regulation of the expression of TSP-1 and VEGF. (PMID:19250552)
• Up-regulation in RRM2 expression levels coupled with its nuclear recruitment suggests an active role for ribonucleotide reductase in the cellular response to camptothecin-mediated DNA damage (PMID:19416980)
• thymidylate synthase/ribonucleotide reductase gene silencing and deoxycytidine kinase::uridine monophosphate kinase fusion gene gene overexpression markedly improved gemcitabine’s therapeutic activity (PMID:19568409)
• Data show that cases with high RRM2 expression had a shorter OS than cases with low RRM2 levels. (PMID:19639316)
• we provide molecular evidence for a new mechanism of HBV-host cell interaction where RNR-R2, a critical cell-cycle gene, is selectively activated in nonproliferating cells. (PMID:20155784)
• This study correlates the distinct catalytic mechanisms of the small subunits hp53R2 and hRRM2 with a hydrogen-bonding network. (PMID:20484015)
• Ribonucleotide reductase M2 subunit overexpression could be associated with the gastric cancer progression. (PMID:20825972)
• High RRM2 is associated with gemcitabine resistance in pancreatic cancer. (PMID:20927319)
• We have shown frequent overexpression of RRM2 protein and its possible role in bladder cancer. (PMID:21166702)
• Data suggest ribonucleotide reductase A site binding with inhibitor. (PMID:21628579)
• HDM-2 inhibition suppresses expression of ribonucleotide reductase subunit M2, and synergistically enhances gemcitabine-induced cytotoxicity in mantle cell lymphoma. (PMID:21844567)
• Under serum-starved conditions, the expression level of RRM2 protein increased in HCT116 cells compared to HKe3 cells (HCT116 cells with a disruption in oncogenic KRAS), and the re-expression of KRAS in HKe3 cells induced the expression of RRM2. (PMID:21873171)
• Knockdown of the ribonucleotide RR2 subunit leads to decreased cisplatin-induced gap-filling synthesis in nucleotide excision repair and a reduced 2’-deoxyadenosine triphosphate (dATP) level in the G2/M phase of the cell cycle. (PMID:21875941)
• p53R2 expression seems more important than that of hRRM2 in prognosis of early-stage lung cancer. (PMID:21965764)
• Recombinant RRM2 translocates from the cytoplasm to the nucleus in a time-dependent manner, leading to stabilization of urokinase mRNA. Overexpression of RRM2 inhibits urokinase protein and mRNA expression through destabilization of uPA mRNA. (PMID:22166006)
• High tumor expression of RRM2 and ERCC1 are associated with reduced recurrence free survival and overall survival after resection of pancreas cancer. (PMID:22569992)
• After DNA damage, cyclin F is downregulated in an ATR-dependent manner to allow accumulation of RRM2. Defective elimination of cyclin F delays DNA repair and sensitizes cells to DNA damage, a phenotype that is reverted by expressing a nondegradable RRM2 mutant. (PMID:22632967)
• RRM2 protein expression in pancreatic adenocarcinoma is neither prognostic nor predictive of adjuvant gemcitabine benefit in patients with resectable pancreatic adenocarcinoma. (PMID:22670179)
• RRM2 expression closely correlates with the development of ovarian tumor and may serve as a novel predictive marker for diagnosis and prognosis of the disease. (PMID:22884145)
• RRM2 may be a facilitating factor in colorectal tumorigenesis and UV-induced DNA damage repair. (PMID:23002339)
• Report essential roles for ribonucleotide reductase and thymidylate synthase in C-MYC-dependent suppression of senescence in melanoma cells. (PMID:23249808)
• RRM2 was found to be a key determinant of both inherent and acquired gemcitabine with reduced let-7 expression likely to contribute to RRM2-mediated inherent chemoresistance in poorly differentiated pancreatic cancer cells. (PMID:23335963)
• RRM2 small interfering RNA-mediated treatment is an effective strategy to inverse chemosensitivity of tumor cells to cisplatin, enhance the efficacy of Gem-induced cytotoxicity and promote apoptosis of cisplatin-resistant ovarian cancer cells in vitro. (PMID:23466567)
• The crystal structure of RRM1/2 complexed with target mRNA has been solved; comparison of the two structures show that RNA-binding protein RRM1/2 undergoes conformational changes upon RNA binding. (PMID:23519412)
• Our novel findings add to the knowledge of RRM2 in regulating expression of the antiapoptotic protein Bcl-2 and reveal a critical link between RRM2 and Bcl-2 in apoptosis signaling. (PMID:23719266)
• These results suggest that SNPs within ribonucleotide reductase (RRM1 and RRM2) might be helpful predictive markers of response to nucleoside analogs and should be further validated in larger cohorts. (PMID:24024897)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	rrm2	ENSDARG00000020711
danio_rerio	RRM2	ENSDARG00000078069
mus_musculus	Rrm2	ENSMUSG00000020649
rattus_norvegicus	Rrm2	ENSRNOG00000054286
rattus_norvegicus		ENSRNOG00000088764
drosophila_melanogaster	RnrS	FBGN0011704
caenorhabditis_elegans		WBGENE00004392

Paralogs (1): RRM2B (ENSG00000048392)

Protein

Protein identifiers

Ribonucleoside-diphosphate reductase subunit M2 — P31350 (reviewed: P31350)

Alternative names: Ribonucleotide reductase small chain, Ribonucleotide reductase small subunit

All UniProt accessions (4): P31350, A0A286YFD6, A0A2R8Y837, A0A7P0SBL1

UniProt curated annotations — full annotation on UniProt →

Function. Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides. Inhibits Wnt signaling.

Subunit / interactions. Heterodimer of a large and a small subunit. Interacts (via Cy motif and when phosphorylated at Thr-33) with CCNF; the interaction occurs exclusively in G2 and early M.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Phosphorylation on Ser-20 relieves the inhibitory effect on Wnt signaling. Phosphorylated on Thr-33 by CDK1 and CDK2; predominantly in G2 and M phase. Ubiquitinated by the SCF(CCNF) E3 ubiquitin-protein ligase complex; leading to its degradation by the proteasome.

Cofactor. Binds 2 iron ions per subunit.

Induction. Up-regulated in response to DNA damage induced by doxorubicin, camptothecin, UV-C, methyl methanesulfonate, nocodazole, or gamma-irradiation.

Miscellaneous. Two distinct regulatory sites have been defined: the specificity site, which controls substrate specificity, and the activity site which regulates overall catalytic activity. A substrate-binding catalytic site, located on M1, is formed only in the presence of the second subunit M2.

Similarity. Belongs to the ribonucleoside diphosphate reductase small chain family.

Isoforms (2)

UniProt ID	Names	Canonical?
P31350-1	1	yes
P31350-2	2

RefSeq proteins (2): NP_001025, NP_001159403 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000358	RNR_small_fam	Family
IPR009078	Ferritin-like_SF	Homologous_superfamily
IPR012348	RNR-like	Homologous_superfamily
IPR030475	RNR_small_AS	Active_site
IPR033909	RNR_small	Family

Pfam: PF00268

Enzyme classification (BRENDA):

• EC 1.17.4.1 — ribonucleoside-diphosphate reductase (BRENDA: 56 organisms, 130 substrates, 474 inhibitors, 39 Km, 9 kcat entries)

Substrate kinetics (BRENDA)

10 substrates with measured Km, best-characterized 10. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
CDP	0.0005–0.31	14
ADP	0.0078–0.3	6
GDP	0.0012–0.37	4
UDP	0.08–1.2	4
ATP	0.07	1
DATP	0.003	1
DTTP	0.0015	1
GLUTAREDOXIN	0.0001	1
GLUTAREDOXIN 1	0.006	1
THIOREDOXIN	0.003	1

Catalyzed reactions (Rhea), 1 shown:

• a 2’-deoxyribonucleoside 5’-diphosphate + [thioredoxin]-disulfide + H2O = a ribonucleoside 5’-diphosphate + [thioredoxin]-dithiol (RHEA:23252)

UniProt features (40 total): helix 17, binding site 7, mutagenesis site 4, turn 3, modified residue 2, sequence conflict 2, chain 1, short sequence motif 1, splice variant 1, active site 1, strand 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
3OLJ	X-RAY DIFFRACTION	2.1
3VPN	X-RAY DIFFRACTION	2.25
3VPO	X-RAY DIFFRACTION	2.3
3VPM	X-RAY DIFFRACTION	2.7
2UW2	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P31350-F1	80.54	0.64

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 176

Ligand- & substrate-binding residues (7): 138; 169; 169; 172; 232; 266; 269

Post-translational modifications (2): 20, 33

Mutagenesis-validated functional residues (4):

Position	Phenotype
20	enhances inhibitory effect on wnt signaling.
20	prevents inhibitory effect on wnt signaling.
33	strongly reduces the interaction with ccnf. lack of proteasomal degradation. increase in the cellular concentration of d
49–51	abolishes the interaction with ccnf. lack of proteasomal degradation. increase in the cellular concentration of datp and

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-499943	Interconversion of nucleotide di- and triphosphates
R-HSA-69205	G1/S-Specific Transcription
R-HSA-8953750	Transcriptional Regulation by E2F6

MSigDB gene sets: 0 (showing top):

GO Biological Process (9): blastocyst development (GO:0001824), DNA repair (GO:0006281), ribonucleoside diphosphate metabolic process (GO:0009185), deoxyribonucleotide biosynthetic process (GO:0009263), 2’-deoxyribonucleotide biosynthetic process (GO:0009265), protein heterotetramerization (GO:0051290), positive regulation of G1/S transition of mitotic cell cycle (GO:1900087), deoxyribonucleotide metabolic process (GO:0009262), positive regulation of mitotic cell cycle phase transition (GO:1901992)

GO Molecular Function (7): ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor (GO:0004748), ferric iron binding (GO:0008199), protein homodimerization activity (GO:0042803), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), identical protein binding (GO:0042802), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), ribonucleoside-diphosphate reductase complex (GO:0005971), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Metabolism of nucleotides	1
G1/S Transition	1
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
in utero embryonic development	1
anatomical structure development	1
DNA metabolic process	1
DNA damage response	1
nucleoside diphosphate metabolic process	1
biosynthetic process	1
deoxyribonucleotide metabolic process	1
nucleotide biosynthetic process	1
2’-deoxyribonucleotide metabolic process	1
deoxyribose phosphate biosynthetic process	1
protein tetramerization	1
protein heterooligomerization	1
G1/S transition of mitotic cell cycle	1
positive regulation of mitotic cell cycle phase transition	1
positive regulation of cell cycle G1/S phase transition	1
regulation of G1/S transition of mitotic cell cycle	1
metabolic process	1
mitotic cell cycle phase transition	1
positive regulation of mitotic cell cycle	1
positive regulation of cell cycle phase transition	1
regulation of mitotic cell cycle phase transition	1
ribonucleoside-diphosphate reductase activity	1
iron ion binding	1
identical protein binding	1
protein dimerization activity	1
binding	1
catalytic activity	1
protein binding	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
cytosol	1
oxidoreductase complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

3306 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RRM2	RRM1	P23921	999
RRM2	RAVER1	Q8IY67	931
RRM2	RRM2B	Q7LG56	893
RRM2	EIF4G1	Q04637	841
RRM2	CELF3	Q5SZQ8	831
RRM2	CCNB2	O95067	808
RRM2	CDK1	P06493	808
RRM2	CELF6	Q96J87	801
RRM2	TOP2A	P11388	785
RRM2	TARDBP	Q13148	758
RRM2	AURKA	O14965	757
RRM2	UBE2C	O00762	749
RRM2	NUSAP1	Q9BXS6	747
RRM2	CCNB1	P14635	739
RRM2	CEP55	Q53EZ4	739

IntAct

78 interactions, top by confidence:

A	B	Type	Score
RRM1	RRM2	psi-mi:“MI:0407”(direct interaction)	0.850
RRM2	RRM1	psi-mi:“MI:0914”(association)	0.850
RRM2	RRM1	psi-mi:“MI:0915”(physical association)	0.850
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CCNF	RRM2	psi-mi:“MI:0914”(association)	0.710
RRM2	CCNF	psi-mi:“MI:0403”(colocalization)	0.710
CCNF	RRM2	psi-mi:“MI:0915”(physical association)	0.710
RRM2	FZR1	psi-mi:“MI:0915”(physical association)	0.710
RRM2	CCNF	psi-mi:“MI:0915”(physical association)	0.710
FAF2	UBB	psi-mi:“MI:0914”(association)	0.640
RRM2	HSPA8	psi-mi:“MI:0914”(association)	0.640
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
SDCBP	RRM2	psi-mi:“MI:0915”(physical association)	0.560
RRM2	INPPL1	psi-mi:“MI:0914”(association)	0.530
RRM1	GLRX3	psi-mi:“MI:0914”(association)	0.530
RRM2	CDC27	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530

BioGRID (162): RRM2 (Two-hybrid), RRM2 (Affinity Capture-MS), INPPL1 (Affinity Capture-MS), FZR1 (Affinity Capture-MS), CDC27 (Affinity Capture-MS), ANAPC4 (Affinity Capture-MS), RRM2 (Affinity Capture-MS), CSTF1 (Co-fractionation), NPLOC4 (Co-fractionation), RRM2 (Co-fractionation), RRM2 (Co-fractionation), RRM2 (Co-fractionation), RRM2 (Co-fractionation), RRM2 (Co-fractionation), RRM2 (Co-fractionation)

ESM2 similar proteins: A0A365, A0QHM5, A0QX51, A1KIW9, A4FIS6, B1W5F4, B8ZR76, O88956, P00165, P16298, P20651, P31350, P37273, P48452, P48453, P63328, P63329, P65263, P9WK98, P9WK99, Q06GW7, Q06RA2, Q08209, Q0G9I9, Q0G9T2, Q0ZIY9, Q1KXS9, Q2KJ61, Q2PMQ5, Q332U7, Q33C02, Q3C1M5, Q4R7Q7, Q4VZI6, Q5HZM6, Q5RIC0, Q5ZHS1, Q68RX7, Q6ENT4, Q6EW22

Diamond homologs: A0A7H0DN21, O15910, O46310, O57175, P07201, P09938, P0C8I0, P0C8I1, P0C8I2, P0DKH2, P0DKH3, P0DSS7, P0DSS8, P11157, P11158, P20493, P26713, P28847, P29883, P31350, P32209, P36603, P42170, P42492, P42521, P48592, P49723, P49730, P50649, P50650, P50651, P79733, Q4KLN6, Q4R741, Q4R7Q7, Q5R9G0, Q60561, Q6PEE3, Q6R7K3, Q6UDJ1

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
CDK1	down-regulates	RRM2	phosphorylation
clofarabine	“down-regulates activity”	RRM2	“chemical inhibition”
hydroxyurea	“down-regulates activity”	RRM2	“chemical inhibition”
RRM2	“form complex”	“Ribonucleotide reductase”	binding
CDK1	unknown	RRM2	phosphorylation
gemcitabine	“down-regulates activity”	RRM2	“chemical inhibition”
(2R,3S,4S,5R)-2-(6-amino-2-fluoro-9-purinyl)-5-(hydroxymethyl)oxolane-3,4-diol	“down-regulates activity”	RRM2	“chemical inhibition”
YAP1	“up-regulates quantity by expression”	RRM2	“transcriptional regulation”
YAP/TAZ	“up-regulates quantity by expression”	RRM2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 74 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Anchoring of the basal body to the plasma membrane	6	13.8×	1e-03
Regulation of PLK1 Activity at G2/M Transition	5	12.9×	4e-03
Cell Cycle Checkpoints	5	9.0×	7e-03
Clathrin-mediated endocytosis	5	8.7×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
cell division	9	6.6×	5e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

38 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	23
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

864 predictions. Top by Δscore:

Variant	Effect	Δscore
2:10122881:TCGAC:T	donor_gain	1.0000
2:10122896:CG:C	donor_gain	1.0000
2:10122896:CGGTG:C	donor_loss	1.0000
2:10122897:GG:G	donor_gain	1.0000
2:10122897:GGTG:G	donor_loss	1.0000
2:10122898:G:GA	donor_loss	1.0000
2:10122898:G:GG	donor_gain	1.0000
2:10122899:T:A	donor_loss	1.0000
2:10122981:A:AG	acceptor_gain	1.0000
2:10122982:G:GA	acceptor_gain	1.0000
2:10122982:GCC:G	acceptor_gain	1.0000
2:10123053:AGCCG:A	donor_gain	1.0000
2:10123054:GCCG:G	donor_gain	1.0000
2:10123054:GCCGG:G	donor_gain	1.0000
2:10123056:CG:C	donor_gain	1.0000
2:10123057:GG:G	donor_gain	1.0000
2:10123057:GGT:G	donor_loss	1.0000
2:10123058:G:GG	donor_gain	1.0000
2:10123384:CA:C	acceptor_loss	1.0000
2:10123385:A:AG	acceptor_gain	1.0000
2:10123385:AG:A	acceptor_loss	1.0000
2:10123386:G:GT	acceptor_gain	1.0000
2:10123386:GA:G	acceptor_gain	1.0000
2:10123386:GAA:G	acceptor_gain	1.0000
2:10123386:GAAA:G	acceptor_gain	1.0000
2:10123386:GAAAA:G	acceptor_gain	1.0000
2:10123527:GGAG:G	donor_gain	1.0000
2:10123528:GAGG:G	donor_gain	1.0000
2:10123529:AG:A	donor_loss	1.0000
2:10123530:GG:G	donor_loss	1.0000

AlphaMissense

2602 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:10123454:T:A	V81D	1.000
2:10123497:G:C	K95N	1.000
2:10123497:G:T	K95N	1.000
2:10123501:G:C	A97P	1.000
2:10123507:G:C	A99P	1.000
2:10123516:T:A	W102R	1.000
2:10123516:T:C	W102R	1.000
2:10123517:G:C	W102S	1.000
2:10123518:G:C	W102C	1.000
2:10123518:G:T	W102C	1.000
2:10123751:G:C	D112H	1.000
2:10123809:T:A	L131Q	1.000
2:10123809:T:C	L131P	1.000
2:10123814:T:C	F133L	1.000
2:10123816:C:A	F133L	1.000
2:10123816:C:G	F133L	1.000
2:10123817:T:C	F134L	1.000
2:10123819:T:A	F134L	1.000
2:10123819:T:G	F134L	1.000
2:10123821:C:A	A135E	1.000
2:10123826:A:C	S137R	1.000
2:10123828:C:A	S137R	1.000
2:10123828:C:G	S137R	1.000
2:10123829:G:C	D138H	1.000
2:10123829:G:T	D138Y	1.000
2:10123830:A:C	D138A	1.000
2:10123830:A:G	D138G	1.000
2:10123830:A:T	D138V	1.000
2:10123831:T:A	D138E	1.000
2:10123831:T:G	D138E	1.000

dbSNP variants (sampled 300 via entrez): RS1000031006 (2:10136510 C>T), RS1000067893 (2:10189924 A>G), RS1000096638 (2:10192944 G>A), RS1000127073 (2:10152610 G>C), RS1000184138 (2:10133437 C>T), RS1000191125 (2:10167720 C>T), RS1000223902 (2:10134147 G>A), RS1000229118 (2:10139761 CAGAG>C,CAG), RS1000255685 (2:10170866 A>G), RS1000295152 (2:10200416 A>C), RS1000297399 (2:10184283 T>C), RS1000349537 (2:10165022 G>A), RS1000349879 (2:10120711 C>G,T), RS1000382253 (2:10163647 A>G), RS1000436663 (2:10155167 C>A,T)

Disease associations

OMIM: gene MIM:180390 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001942_5	Prostate cancer	3.000000e-08
GCST002720_5	Kidney function decline traits	3.000000e-06
GCST006482_8	Lung function (FEV1/FVC)	9.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1954 (SINGLE PROTEIN), CHEMBL2095215 (PROTEIN COMPLEX GROUP)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 4,524 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL231616	TRIAPINE	3	4,524

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
RRM2 OVEREXPRESSION	Gemcitabine	Pancreatic Cancer	Resistance	CIViC D	EID1860

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1130609	Efficacy	3	cladribine;cytarabine	Leukemia;Myeloid;Acute
rs5030743	Efficacy	3	cladribine;cytarabine	Leukemia;Myeloid;Acute

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1130609	RRM2	3	1.50	1	cladribine;cytarabine
rs5030743	RRM2	3	1.75	1	cladribine;cytarabine
rs1138729	RRM2		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — 1.17.4.1 Ribonucleoside-diphosphate reductases

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
clofarabine	Inhibition	8.3	pIC50
fludarabine	Inhibition	6.0	pIC50
hydroxyurea	Inhibition	3.83	pIC50

Binding affinities (BindingDB)

15 measured of 15 human assays (15 total across all organisms); most potent 15 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(4S)-5-chloro-N-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2-oxo-3H-1,3,4-oxadiazol-5-yl)propyl]-4-hydroxy-4-(trideuteriomethyl)-2,3-dihydrochromene-8-sulfonamide	IC50	30 nM	US-12344588: Sulfonamide compounds and use thereof
5-chloro-N-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2-oxo-3H-1,3,4-oxadiazol-5-yl)propyl]-4-hydroxy-4-(trideuteriomethyl)-2,3-dihydrochromene-8-sulfonamide	IC50	30 nM	US-20250223270: Sulfonamide Compounds and Use Thereof
dimethylphenyl)-1-(5-oxo-4,5-dihydro-	IC50	70 nM	US-20250223270: Sulfonamide Compounds and Use Thereof
(4R)-5-chloro-N-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2-oxo-3H-1,3,4-oxadiazol-5-yl)propyl]-4-hydroxy-4-(trideuteriomethyl)-2,3-dihydrochromene-8-sulfonamide	IC50	80 nM	US-12344588: Sulfonamide compounds and use thereof
(4S)-5-chloro-N-[(1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(2-oxo-3H-1,3,4-oxadiazol-5-yl)propyl]-4-hydroxy-4-(trideuteriomethyl)-2,3-dihydrochromene-8-sulfonamide	IC50	80 nM	US-12344588: Sulfonamide compounds and use thereof
5-chloro-N-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2-oxo-3H-1,3,4-oxadiazol-5-yl)propyl]-4-hydroxy-4-(trideuteriomethyl)-2,3-dihydrochromene-8-sulfonamide	IC50	80 nM	US-20250223270: Sulfonamide Compounds and Use Thereof
5-chloro-N-((1S,2R)-2-(3-chloro-6-	IC50	80 nM	US-20250223270: Sulfonamide Compounds and Use Thereof
5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-	IC50	80 nM	US-20250223270: Sulfonamide Compounds and Use Thereof
(4R)-5-chloro-N-[(1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(2-oxo-3H-1,3,4-oxadiazol-5-yl)propyl]-4-hydroxy-4-(trideuteriomethyl)-2,3-dihydrochromene-8-sulfonamide	IC50	140 nM	US-12344588: Sulfonamide compounds and use thereof
fluoro-2-methylphenyl)-1-(5-oxo-4,5-	IC50	140 nM	US-20250223270: Sulfonamide Compounds and Use Thereof
Triapine	IC50	1200 nM	US-10155732: Ribonucleotide reductase inhibitors and methods of use
N-[4-(3,4-dihydroxyphenyl)-1,3-thiazol-2-yl]-3,4-dihydroxybenzamide	IC50	9300 nM	US-10155732: Ribonucleotide reductase inhibitors and methods of use
N-[4-(3,4-dihydroxyphenyl)-1,3-thiazol-2-yl]benzamide	IC50	15300 nM	US-10155732: Ribonucleotide reductase inhibitors and methods of use
3-[(E)-[4-(3,4-dihydroxyphenyl)-1,3-thiazol-2-yl]iminomethyl]-4-hydroxychromen-2-one	IC50	19100 nM	US-10155732: Ribonucleotide reductase inhibitors and methods of use
Hydroxyurea	IC50	148000 nM	US-10155732: Ribonucleotide reductase inhibitors and methods of use

ChEMBL bioactivities

77 potent at pChembl≥5 of 115 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.22	IC50	0.6	nM	CHEMBL336289
9.15	IC50	0.7	nM	CHEMBL96993
9.00	IC50	1	nM	CHEMBL98729
8.70	IC50	2	nM	CHEMBL1169533
8.52	IC50	3	nM	CHEMBL133754
8.52	IC50	3	nM	CHEMBL305199
8.40	IC50	4	nM	CHEMBL95998
8.30	IC50	5	nM	CHEMBL95766
8.30	IC50	5	nM	CHEMBL335164
8.22	IC50	6	nM	CHEMBL134961
8.19	IC50	6.4	nM	CHEMBL120710
8.15	IC50	7	nM	CHEMBL133827
8.15	IC50	7	nM	CHEMBL37210
8.12	IC50	7.5	nM	CHEMBL431851
7.82	IC50	15	nM	CHEMBL71945
7.75	IC50	18	nM	CHEMBL443029
7.70	IC50	20	nM	CHEMBL1169532
7.66	IC50	22	nM	CHEMBL96993
7.66	IC50	22	nM	CHEMBL439791
7.66	IC50	22	nM	CHEMBL120060
7.62	IC50	24	nM	CHEMBL305229
7.57	IC50	27	nM	CHEMBL131682
7.47	IC50	34	nM	CHEMBL414818
7.44	IC50	36	nM	CHEMBL118524
7.43	IC50	37	nM	CHEMBL98729
7.40	IC50	40	nM	CHEMBL132130
7.37	IC50	43	nM	CHEMBL99950
7.26	IC50	55	nM	CHEMBL1169533
7.21	IC50	61	nM	CHEMBL1790855
7.00	IC50	100	nM	CHEMBL131731
6.91	IC50	123	nM	CHEMBL95998
6.75	IC50	180	nM	CHEMBL19667
6.73	IC50	185	nM	TRIAPINE
6.68	IC50	210	nM	CHEMBL431851
6.47	IC50	340	nM	CHEMBL331870
6.46	IC50	350	nM	CHEMBL280440
6.36	IC50	440	nM	CHEMBL71721
6.35	IC50	450	nM	CHEMBL19766
6.30	IC50	500	nM	CHEMBL132309
6.23	IC50	588	nM	CHEMBL305229
6.09	IC50	820	nM	CHEMBL315999
6.07	IC50	860	nM	CHEMBL121015
6.07	IC50	860	nM	CHEMBL445620
6.06	IC50	880	nM	CHEMBL306879
6.03	IC50	925	nM	CHEMBL305199
6.00	IC50	1000	nM	CHEMBL87471
6.00	IC50	1000	nM	CHEMBL86188
5.89	IC50	1300	nM	CHEMBL314693
5.85	IC50	1400	nM	CHEMBL82809
5.85	IC50	1400	nM	CHEMBL86963

PubChem BioAssay actives

64 with measured affinity, of 376 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-[[(2S)-3-carboxy-2-[[(2S)-2-[[(2S)-3,3-dimethyl-2-(pentan-3-ylcarbamoylamino)butanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]propanoyl]amino]-4,4-dimethylpentanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	0.0006	uM
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(2-benzyl-3-phenylpropanoyl)amino]-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]-3-carboxypropanoyl]amino]-4-methylpentanoic acid	198112: In vitro inhibitory activity against HSV ribonucleotide reductase	ic50	0.0007	uM
1-[(1S)-2-[[(1S)-1-carboxy-3-methylbutyl]amino]-1-[[(2S)-2-[[(2S)-3-methyl-2-[[(2S)-3-methyl-2-(3-phenylpropanoylamino)butanoyl]amino]butanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]-2-oxoethyl]cyclopentane-1-carboxylic acid	198112: In vitro inhibitory activity against HSV ribonucleotide reductase	ic50	0.0010	uM
(2R)-2-[[(2R)-3-carboxy-2-[[(2S)-2-[[(2R)-2-[[(2R,6S)-2,6-dimethylcyclohexyl]carbamoylamino]-3-methylbutanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	0.0020	uM
(2S)-2-[[(2S)-3-carboxy-2-[[(2S)-2-[[(2S)-3,3-dimethyl-2-(pentan-3-ylcarbamoylamino)butanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	0.0030	uM
(2S)-2-[[(2S)-3-carboxy-2-[[(2S)-2-[[(2S)-3,3-dimethyl-2-(pentan-3-ylcarbamoylamino)butanoyl]amino]-5,5-dimethyl-4-oxohexanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	0.0030	uM
(2S)-2-[[(2S)-3-carboxy-2-[[(2S)-2-[[(2S)-3,3-dimethyl-2-[[(2S)-3-methyl-2-(3-phenylpropanoylamino)butanoyl]amino]butanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	198112: In vitro inhibitory activity against HSV ribonucleotide reductase	ic50	0.0040	uM
(2S)-2-[[(2S)-3-carboxy-2-[[(2S)-2-[[(2S)-3-methyl-2-[[(2S)-3-methyl-2-(3-phenylpropanoylamino)butanoyl]amino]butanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]propanoyl]amino]-4,4-dimethylpentanoic acid	198112: In vitro inhibitory activity against HSV ribonucleotide reductase	ic50	0.0050	uM
(2S)-2-[[(2S)-3-carboxy-2-[[(2R,5S)-2-(3,3-dimethyl-2-oxobutyl)-6,6-dimethyl-4-oxo-5-(pentan-3-ylcarbamoylamino)heptanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	0.0050	uM
(3S)-3-[[(2S)-2-[[(2S)-3,3-dimethyl-2-(pentan-3-ylcarbamoylamino)butanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]-4-[[(2S)-1-hydroxy-4,4-dimethylpentan-2-yl]amino]-4-oxobutanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	0.0060	uM
1-[(1S)-2-[[(1S)-1-carboxy-3-methylbutyl]amino]-1-[[(2S)-2-[[(2S)-2-(2-ethylbutanoylamino)-3,3-dimethylbutanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]-2-oxoethyl]cyclopent-3-ene-1-carboxylic acid	198112: In vitro inhibitory activity against HSV ribonucleotide reductase	ic50	0.0064	uM
(2S)-2-[[(2S)-3-carboxy-2-[[(2S)-2-[[(2S)-2-(heptan-4-ylcarbamoylamino)-3-methylbutanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	0.0070	uM
(2S)-2-[[(2S)-3-carboxy-2-[[(2S,5S)-6,6-dimethyl-4-oxo-2-(2-oxo-2-pyrrolidin-1-ylethyl)-5-(pentan-3-ylcarbamoylamino)heptanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	0.0070	uM
(2S)-2-[[(2S)-3-carboxy-2-[[(2S)-2-[[(2S)-3-methyl-2-[[(2S)-3-methyl-2-[methyl(3-phenylpropanoyl)amino]butanoyl]amino]butanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	198112: In vitro inhibitory activity against HSV ribonucleotide reductase	ic50	0.0075	uM
(2S)-2-[[(2S)-3-carboxy-2-[[(2S)-2-[[(2S)-3-methyl-2-(pentan-3-ylcarbamoylamino)butanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	0.0150	uM
(3S)-4-[[(3R)-2,2-dimethylpentan-3-yl]amino]-3-[[(2S)-2-[[(2S)-3,3-dimethyl-2-(pentan-3-ylcarbamoylamino)butanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]-4-oxobutanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	0.0180	uM
(2R)-2-[[(2R)-3-carboxy-2-[[(2S)-2-[[(2R)-2-[[(2S,6S)-2,6-dimethylcyclohexyl]carbamoylamino]-3-methylbutanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]propanoyl]amino]-4-methylpentanoic acid;(2R)-2-[[(2R)-3-carboxy-2-[[(2S)-2-[[(2R)-2-[[(2R,6R)-2,6-dimethylcyclohexyl]carbamoylamino]-3-methylbutanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	0.0200	uM
(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[(2-benzyl-3-phenylpropanoyl)-methylamino]-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-4-oxobutanoyl]amino]-3-carboxypropanoyl]amino]-4-methylpentanoic acid	198112: In vitro inhibitory activity against HSV ribonucleotide reductase	ic50	0.0220	uM
(2S)-2-[[(2S)-3-carboxy-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-cyclohexyl-2-(3-phenylpropanoylamino)acetyl]amino]-3-methylbutanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	198112: In vitro inhibitory activity against HSV ribonucleotide reductase	ic50	0.0220	uM
(2S)-2-[[(2S)-3-carboxy-2-[[(2S)-2-[[(2S)-3-methyl-2-[[(2S)-3-methyl-2-(3-phenylpropanoylamino)butanoyl]amino]butanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	0.0240	uM
(3S)-4-[[(2R)-3,3-dimethylbutan-2-yl]amino]-3-[[(2S)-2-[[(2S)-3,3-dimethyl-2-(pentan-3-ylcarbamoylamino)butanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]-4-oxobutanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	0.0270	uM
(3S)-4-[[(2S)-1-hydroxy-4,4-dimethylpentan-2-yl]amino]-3-[[(2S)-2-[[(2S)-3-methyl-2-[[(2S)-3-methyl-2-(3-phenylpropanoylamino)butanoyl]amino]butanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]-4-oxobutanoic acid	198112: In vitro inhibitory activity against HSV ribonucleotide reductase	ic50	0.0340	uM
(2S)-2-[[(2S)-3-carboxy-2-[[(2S)-2-[[(2S)-2-[[(2S)-3,3-dimethyl-2-(3-phenylpropanoylamino)butanoyl]amino]-3-methylbutanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	198112: In vitro inhibitory activity against HSV ribonucleotide reductase	ic50	0.0360	uM
(3S)-3-[[(2S)-2-[[(2S)-3,3-dimethyl-2-(pentan-3-ylcarbamoylamino)butanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]-4-(2,2-dimethylpropylamino)-4-oxobutanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	0.0400	uM
(3S)-4-[[(1S)-1-carboxy-3-methylbutyl]amino]-3-[[(2S)-2-[[(2S)-2-(2-ethylbutanoylamino)-3,3-dimethylbutanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]-2,2-dimethyl-4-oxobutanoic acid	198112: In vitro inhibitory activity against HSV ribonucleotide reductase	ic50	0.0430	uM
(2S)-2-[[(2S)-3-carboxy-2-[[(2S)-2-[[(2S)-3-methyl-2-[[(2S,3S)-3-methyl-2-(3-phenylpropanoylamino)pentanoyl]amino]butanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	198112: In vitro inhibitory activity against HSV ribonucleotide reductase	ic50	0.0610	uM
(3S)-4-(3,3-dimethylbutylamino)-3-[[(2S)-2-[[(2S)-3,3-dimethyl-2-(pentan-3-ylcarbamoylamino)butanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]-4-oxobutanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	0.1000	uM
(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[(2-benzyl-3-phenylpropanoyl)amino]-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-4-oxobutanoyl]amino]-3-carboxypropanoyl]amino]-4-methylpentanoic acid	198112: In vitro inhibitory activity against HSV ribonucleotide reductase	ic50	0.1800	uM
[(E)-(3-amino-2-pyridinyl)methylideneamino]thiourea	1472802: Inhibition of human RRM2 expressed in Escherichia coli BL21-codon plus(DE3) using [14C]-ADP as substrate after 3 mins by liquid scintillation counting method	ic50	0.1850	uM
(2S)-2-[[(2S)-3-carboxy-2-[[(2S)-2-[[(2S)-3-methyl-2-[[(2S)-2-(3-phenylpropanoylamino)butanoyl]amino]butanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	198112: In vitro inhibitory activity against HSV ribonucleotide reductase	ic50	0.3400	uM
(3S)-3-[[(2S)-2-[[(2S)-3,3-dimethyl-2-(pentan-3-ylcarbamoylamino)butanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]-4-(3-methylbutylamino)-4-oxobutanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	0.3500	uM
(2S)-2-[[(2S)-3-carboxy-2-[[(2S)-2-[[(2S)-3-methyl-2-(propan-2-ylcarbamoylamino)butanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	0.4400	uM
(2S)-2-[[(2S)-3-carboxy-2-[[(2S)-2-[[(2S)-2-(cyclohexylcarbamoylamino)-3-methylbutanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	0.5000	uM
[(5-amino-6-formyl-2-pyridinyl)amino]thiourea	197981: Inhibitory activity against CDP reductase.	ic50	0.8200	uM
(2S)-2-[[(2S)-3-carboxy-2-[[(2S)-2-[[(2S)-2-(2-ethylbutanoylamino)-3-methylbutanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	0.8600	uM
(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-3-methyl-2-[[(2S)-3-methyl-2-[[(2R)-2-methyl-3-phenylpropanoyl]amino]butanoyl]amino]butanoyl]amino]-4-oxobutanoyl]amino]-3-carboxypropanoyl]amino]-4-methylpentanoic acid	198112: In vitro inhibitory activity against HSV ribonucleotide reductase	ic50	0.8600	uM
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]-3-carboxypropanoyl]amino]-4-methylpentanoic acid	198112: In vitro inhibitory activity against HSV ribonucleotide reductase	ic50	0.8800	uM
[(E)-[5-(ethylamino)-2-pyridinyl]methylideneamino]thiourea	197981: Inhibitory activity against CDP reductase.	ic50	1.0000	uM
[(E)-[3-(methylamino)-2-pyridinyl]methylideneamino]thiourea	197981: Inhibitory activity against CDP reductase.	ic50	1.0000	uM
[(E)-[5-(methylamino)-2-pyridinyl]methylideneamino]thiourea	197981: Inhibitory activity against CDP reductase.	ic50	1.3000	uM
[(E)-[5-(propylamino)-2-pyridinyl]methylideneamino]thiourea	197981: Inhibitory activity against CDP reductase.	ic50	1.4000	uM
[(E)-[5-(prop-2-enylamino)-2-pyridinyl]methylideneamino]thiourea	197981: Inhibitory activity against CDP reductase.	ic50	1.4000	uM
[(E)-[3-(prop-2-enylamino)-2-pyridinyl]methylideneamino]thiourea	197981: Inhibitory activity against CDP reductase.	ic50	1.7000	uM
(3S)-3-[[(2S)-2-[[(2S)-3-carboxy-2-[[(2S)-2-[[2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-2-phenylacetyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-3-cyclohexylpropanoyl]amino]-4-[[(1S)-1-carboxy-2-phenylethyl]amino]-4-oxobutanoic acid	242343: Inhibition of mammalian ribonucleotide reductase in a standard dTTP-dependent GDP reductase assay	ic50	1.9000	uM
(3S)-3-[[(2S)-2-[[(2S)-3,3-dimethyl-2-(pentan-3-ylcarbamoylamino)butanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]-4-(2-methylpropylamino)-4-oxobutanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	1.9000	uM
(3S)-4-[[(3S)-2,2-dimethylpentan-3-yl]amino]-3-[[(2S)-2-[[(2S)-3,3-dimethyl-2-(pentan-3-ylcarbamoylamino)butanoyl]amino]-4-oxo-4-pyrrolidin-1-ylbutanoyl]amino]-4-oxobutanoic acid	197982: Inhibitory effect was evaluated on Herpes simplex virus (HSV) ribonucleotide reductase (RR) enzyme.	ic50	2.0000	uM
(4S)-5-[[(2S)-1-[[(2S)-3-carboxy-1-[[(1S)-1-carboxy-2-phenylethyl]amino]-1-oxopropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]-4-[[(2S)-2-[[3-(9H-fluoren-9-ylmethoxy)-3-oxo-2-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-5-oxopentanoic acid	242343: Inhibition of mammalian ribonucleotide reductase in a standard dTTP-dependent GDP reductase assay	ic50	2.4000	uM
(3S)-3-[[(2S)-2-[[(2S)-3-carboxy-2-[[(2S)-2-[[3-(9H-fluoren-9-ylmethoxy)-3-oxo-2-phenylpropanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-3-cyclohexylpropanoyl]amino]-4-[[(1S)-1-carboxy-2-phenylethyl]amino]-4-oxobutanoic acid	242343: Inhibition of mammalian ribonucleotide reductase in a standard dTTP-dependent GDP reductase assay	ic50	2.4000	uM
[(E)-[5-(butylamino)-2-pyridinyl]methylideneamino]thiourea	197981: Inhibitory activity against CDP reductase.	ic50	2.5000	uM
[(E)-[5-(aminomethyl)-2-pyridinyl]methylideneamino]thiourea	197981: Inhibitory activity against CDP reductase.	ic50	2.5000	uM

CTD chemical–gene interactions

162 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, decreases expression, increases expression	7
Fluorouracil	affects expression, decreases expression, increases expression, affects cotreatment, affects response to substance	7
bisphenol A	affects expression, affects cotreatment, increases methylation, decreases expression, increases expression	6
Benzo(a)pyrene	affects methylation, decreases expression	5
Estradiol	decreases expression, increases expression, affects cotreatment	5
Cyclosporine	affects expression, decreases expression	5
Doxorubicin	affects expression, decreases expression, affects cotreatment, affects response to substance	4
Cisplatin	increases expression, decreases reaction, increases activity, increases phosphorylation, increases reaction (+1 more)	3
Progesterone	affects cotreatment, decreases expression, increases expression	3
Silicon Dioxide	decreases expression, increases expression	3
Tetrachlorodibenzodioxin	increases expression, affects expression, decreases expression	3
Valproic Acid	affects expression, decreases expression, increases methylation	3
Genistein	increases expression, decreases expression	3
cobaltous chloride	decreases expression	2
perfluorooctanoic acid	decreases expression	2
Resveratrol	affects cotreatment, increases expression, decreases expression	2
Arsenic Trioxide	decreases expression	2
Gemcitabine	decreases response to substance, increases expression, affects response to substance	2
Copper	affects binding, increases expression, decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Tretinoin	decreases expression	2
Aflatoxin B1	affects expression, affects cotreatment, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression	2
aristolochic acid I	decreases expression, increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases reaction, increases degradation, decreases expression	1
afuresertib	decreases expression	1
FR900359	decreases phosphorylation	1
bismuth tripotassium dicitrate	decreases expression	1
tungsten carbide	increases expression, affects cotreatment	1

ChEMBL screening assays

37 unique, capped per target: 34 binding, 3 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4027846	Binding	Inhibition of human RRM2 expressed in Escherichia coli BL21-codon plus(DE3) using [14C]-ADP as substrate after 3 mins by liquid scintillation counting method	Structure-Guided Synthesis and Mechanistic Studies Reveal Sweetspots on Naphthyl Salicyl Hydrazone Scaffold as Non-Nucleosidic Competitive, Reversible Inhibitors of Human Ribonucleotide Reductase. — J Med Chem
CHEMBL652605	Functional	Inhibitory activity against HSV-1 in baby hamster kidney cell	Peptidomimetic inhibitors of herpes simplex virus ribonucleotide reductase: a new class of antiviral agents. — J Med Chem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.