Adrenal cortex carcinoma

Summary

Adrenal cortex carcinoma (MONDO:0006639) is a cancer with 2 cohort genes (2 CIViC-evidence somatic drivers; 21 ClinVar predisposition records) and 86 clinical trials. Top therapeutic interventions include cabozantinib, mitotane, and cisplatin.

At a glance

• Classification: Cancer
• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 21
• Phenotypes (HPO): 29
• Clinical trials: 86

Clinical features

Epidemiology

Prevalence records

25 prevalence record(s), Orphanet, top 20 (validated / broadest geography first):

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.75	Europe	Validated
Annual incidence	<1 / 1 000 000	0.082	Portugal	Validated
Annual incidence	1-9 / 1 000 000	0.173	Austria	Validated
Annual incidence	1-9 / 1 000 000	0.18	Belgium	Validated
Annual incidence	1-9 / 1 000 000	0.249	Bulgaria	Validated
Annual incidence	1-9 / 1 000 000	0.547	Croatia	Validated
Annual incidence	1-9 / 1 000 000	0.271	Czech Republic	Validated
Annual incidence	1-9 / 1 000 000	0.314	Estonia	Validated
Annual incidence	1-9 / 1 000 000	0.225	Finland	Validated
Annual incidence	1-9 / 1 000 000	0.173	Germany	Validated
Annual incidence	1-9 / 1 000 000	0.17	Iceland	Validated
Annual incidence	1-9 / 1 000 000	0.133	Ireland	Validated
Annual incidence	1-9 / 1 000 000	0.288	Italy	Validated
Annual incidence	1-9 / 1 000 000	0.514	Latvia	Validated
Annual incidence	1-9 / 1 000 000	0.464	Lithuania	Validated
Annual incidence	1-9 / 1 000 000	0.188	Malta	Validated
Annual incidence	1-9 / 1 000 000	0.226	Norway	Validated
Annual incidence	1-9 / 1 000 000	0.433	Poland	Validated
Annual incidence	1-9 / 1 000 000	0.234	Slovakia	Validated
Annual incidence	1-9 / 1 000 000	0.244	Slovenia	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0006744	Adrenocortical carcinoma	Obligate (100%)
HP:0000080	Abnormality of reproductive system physiology	Frequent (30-79%)
HP:0000737	Irritability	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0000819	Diabetes mellitus	Frequent (30-79%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0000859	Hyperaldosteronism	Frequent (30-79%)
HP:0000975	Hyperhidrosis	Frequent (30-79%)
HP:0000998	Hypertrichosis	Frequent (30-79%)
HP:0001065	Striae distensae	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001824	Weight loss	Frequent (30-79%)
HP:0001939	Abnormality of metabolism/homeostasis	Frequent (30-79%)
HP:0001962	Palpitations	Frequent (30-79%)
HP:0002027	Abdominal pain	Frequent (30-79%)
HP:0002900	Hypokalemia	Frequent (30-79%)
HP:0003118	Increased circulating cortisol level	Frequent (30-79%)
HP:0003466	Paradoxical increased cortisol secretion on dexamethasone suppression test	Frequent (30-79%)
HP:0004324	Increased body weight	Frequent (30-79%)
HP:0011748	Adrenocorticotropic hormone deficiency	Frequent (30-79%)
HP:0012030	Increased urinary cortisol level	Frequent (30-79%)
HP:0025134	Increased serum estradiol	Frequent (30-79%)
HP:0025269	Panic attack	Frequent (30-79%)
HP:0025380	Increased circulating androstenedione concentration	Frequent (30-79%)
HP:0025436	Elevated serum 11-deoxycortisol	Frequent (30-79%)
HP:0030078	Lung adenocarcinoma	Frequent (30-79%)
HP:0030348	Increased circulating androgen concentration	Frequent (30-79%)
HP:0500022	Abnormal serum dehydroepiandrosterone level	Frequent (30-79%)
HP:0003110	Abnormality of urine homeostasis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	adrenal cortex carcinoma
Mondo ID	MONDO:0006639
EFO	EFO:1000796
Orphanet	1501
DOID	DOID:3948, DOID:3959, DOID:660
ICD-11	114092945
NCIT	C9325
SNOMED CT	255035007
UMLS	C0206686
MedGen	104917
GARD	0000558
MedDRA	10001388
NORD	733
Anatomy (UBERON)	UBERON:0001235
Is cancer (heuristic)	yes

Also known as: ACC · adenocarcinoma, adrenocortical, malignant · adrenal cortex adenocarcinoma · adrenal cortex cancer · adrenal cortex carcinoma · adrenal cortical adenocarcinoma · adrenal cortical carcinoma · adrenal cortical carcinoma (morphologic abnormality) · adrenal cortical tumors · adrenal cortical tumours · adrenocortical cancer · adrenocortical carcinoma · adrenocortical carcinoma (disease) · cancer of the adrenal cortex · carcinoma of adrenal cortex · carcinoma of the adrenal cortex · carcinoma, adrenocortical, malignant · cortical cell carcinoma · malignant adrenocortical tumor · malignant adrenocortical tumour (+3 more)

Data availability: 21 ClinVar variants · 1 HPO phenotype · 23 cell lines · 16 intOGen driver records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › cancer › cardiovascular cancer › vascular cancer › adrenal cortex carcinoma

Related subtypes (6): choroid plexus cancer, malignant jugulotympanic paraganglioma, choroid cancer, epithelioid hemangioendothelioma, angiosarcoma, great vessel cancer

Subtypes (1): adrenocortical carcinoma, hereditary

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

21 retrieved; paginated sample, class counts are floors:

10 pathogenic, 5 pathogenic/likely pathogenic, 3 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 conflicting classifications of pathogenicity; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
12352	NM_000546.6(TP53):c.747G>T (p.Arg249Ser)	TP53	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12356	NM_000546.6(TP53):c.743G>A (p.Arg248Gln)	TP53	Pathogenic	reviewed by expert panel
127817	NM_000546.6(TP53):c.580C>T (p.Leu194Phe)	TP53	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
127819	NM_000546.6(TP53):c.659A>G (p.Tyr220Cys)	TP53	Pathogenic	reviewed by expert panel
186451	NM_000546.6(TP53):c.527G>A (p.Cys176Tyr)	TP53	Pathogenic	criteria provided, multiple submitters, no conflicts
2584755	NM_000546.6(TP53):c.652del (p.Val218fs)	TP53	Pathogenic	criteria provided, single submitter
376559	NM_000546.6(TP53):c.404G>T (p.Cys135Phe)	TP53	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
406579	NM_000546.6(TP53):c.574C>T (p.Gln192Ter)	TP53	Pathogenic	criteria provided, multiple submitters, no conflicts
406597	NM_000546.6(TP53):c.329G>T (p.Arg110Leu)	TP53	Pathogenic	reviewed by expert panel
428884	NM_000546.6(TP53):c.313G>A (p.Gly105Ser)	TP53	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
578988	NM_000546.6(TP53):c.378C>G (p.Tyr126Ter)	TP53	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
634687	NM_000546.6(TP53):c.538G>T (p.Glu180Ter)	TP53	Pathogenic	criteria provided, single submitter
634754	NM_000546.6(TP53):c.661G>T (p.Glu221Ter)	TP53	Pathogenic	criteria provided, multiple submitters, no conflicts
634766	NM_000546.6(TP53):c.993+1G>T	TP53	Pathogenic	criteria provided, single submitter
634785	NM_000546.6(TP53):c.437G>A (p.Trp146Ter)	TP53	Pathogenic	criteria provided, multiple submitters, no conflicts
12375	NM_000546.6(TP53):c.1031T>C (p.Leu344Pro)	TP53	Likely pathogenic	reviewed by expert panel
184863	NM_000546.6(TP53):c.413C>T (p.Ala138Val)	TP53	Likely pathogenic	reviewed by expert panel
2584754	NM_000546.6(TP53):c.722_724del (p.Ser241del)	TP53	Likely pathogenic	no assertion criteria provided
5591	NM_007194.4(CHEK2):c.470T>C (p.Ile157Thr)	CHEK2	Conflicting classifications of pathogenicity; risk factor	criteria provided, conflicting classifications
265357	NM_000546.6(TP53):c.734G>C (p.Gly245Ala)	TP53	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
428887	NM_000546.6(TP53):c.470T>C (p.Val157Ala)	TP53	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 25 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
TP53	LoF	ACC,ALL,AML,ANGS,ANSC,BCC,BL,BLADDER,BLCA,BRCA,CCRCC,CEAD,CESC,CHOL,CHRCC,CLLSLL,COAD,COADREAD,CSCC,DLBCLNOS,EGC,ES,ESCA,ESCC,GB,GBC,GBM,GIST,HCC,HGGNOS,HNSC,LGGNOS,LIPO,LMS,LNM,LUAD,LUSC,MBL,MEL,MLYM,MT,NBL,NETNOS,NHL,NPC,NSCLC,OS,OVT,PAAD,PANCREAS,PAST,PCM,PLMESO,PRAD,PRCC,PROSTATE,RCC,READ,SACA,SARCNOS,SCLC,SIC,SKCM,SKIN,SOFT_TISSUE,STAD,STOMACH,THYM,UCEC,UCS,UTUC,VULVA,WDTC,WT	CIViC #45
CHEK2	Act	BRCA	CIViC #8950

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TP53	Orphanet:1333	Familial pancreatic carcinoma
TP53	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
TP53	Orphanet:1501	Adrenocortical carcinoma
TP53	Orphanet:210159	Adult hepatocellular carcinoma
TP53	Orphanet:251576	Gliosarcoma
TP53	Orphanet:251579	Giant cell glioblastoma
TP53	Orphanet:251899	Choroid plexus carcinoma
TP53	Orphanet:2807	Papilloma of choroid plexus
TP53	Orphanet:293199	Pleomorphic rhabdomyosarcoma
TP53	Orphanet:3318	Essential thrombocythemia
TP53	Orphanet:524	Li-Fraumeni syndrome
TP53	Orphanet:52688	Myelodysplastic syndrome
TP53	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
TP53	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
TP53	Orphanet:668	Osteosarcoma
TP53	Orphanet:67038	B-cell chronic lymphocytic leukemia
TP53	Orphanet:70573	Small cell lung cancer
TP53	Orphanet:96253	Cushing disease
TP53	Orphanet:99756	Alveolar rhabdomyosarcoma
TP53	Orphanet:99757	Embryonal rhabdomyosarcoma
CHEK2	Orphanet:1331	Familial prostate cancer
CHEK2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
CHEK2	Orphanet:440437	Familial colorectal cancer Type X
CHEK2	Orphanet:524	Li-Fraumeni syndrome
CHEK2	Orphanet:668	Osteosarcoma

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	clinvar,civic_evidence
CHEK2	HGNC:16627	ENSG00000183765	O96017	Serine/threonine-protein kinase Chk2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TP53	Cellular tumor antigen p53	Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence.
CHEK2	Serine/threonine-protein kinase Chk2	Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	13.9×	0.142
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TP53	Transcription factor	no		p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn
CHEK2	Kinase	yes	2.7.11.1	FHA_dom, Prot_kinase_dom, Ser/Thr_kinase_AS

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ganglionic eminence	1
tendon of biceps brachii	1
ventricular zone	1
lower esophagus mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TP53	223	ubiquitous	marker	ventricular zone, ganglionic eminence, tendon of biceps brachii
CHEK2	183	ubiquitous	marker	primordial germ cell in gonad, lower esophagus mucosa, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP53	22,736
CHEK2	4,795

Intra-cohort edges

A	B	Sources
CHEK2	TP53	intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TP53	P04637	313
CHEK2	O96017	38

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 48. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Stabilization of p53	2	761.3×	8e-05	TP53, CHEK2
Regulation of TP53 Activity through Methylation	2	543.8×	8e-05	TP53, CHEK2
Regulation of TP53 Degradation	2	292.8×	2e-04	TP53, CHEK2
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	2	146.4×	6e-04	TP53, CHEK2
G2/M DNA damage checkpoint	2	120.2×	6e-04	TP53, CHEK2
Regulation of TP53 Activity through Phosphorylation	2	117.7×	6e-04	TP53, CHEK2
Loss of function of TP53 in cancer due to loss of tetramerization ability	1	5710.0×	0.001	TP53
Regulation of TP53 Expression	1	2855.0×	0.002	TP53
Transcriptional activation of cell cycle inhibitor p21	1	1427.5×	0.004	TP53
Activation of NOXA and translocation to mitochondria	1	951.7×	0.005	TP53
RUNX3 regulates CDKN1A transcription	1	815.7×	0.005	TP53
PI5P Regulates TP53 Acetylation	1	634.4×	0.006	TP53
Activation of PUMA and translocation to mitochondria	1	571.0×	0.006	TP53
TP53 Regulates Transcription of Caspase Activators and Caspases	1	475.8×	0.006	TP53
TP53 Regulates Transcription of Death Receptors and Ligands	1	475.8×	0.006	TP53
Urea cycle	1	439.2×	0.006	TP53
Regulation of TP53 Activity through Association with Co-factors	1	407.9×	0.006	TP53
TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain	1	380.7×	0.006	TP53
TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest	1	356.9×	0.006	TP53
Formation of Senescence-Associated Heterochromatin Foci (SAHF)	1	335.9×	0.006	TP53
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	1	335.9×	0.006	CHEK2
Zygotic genome activation (ZGA)	1	335.9×	0.006	TP53
Regulation of NF-kappa B signaling	1	317.2×	0.007	TP53
TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest	1	300.5×	0.007	TP53
SUMOylation of transcription factors	1	285.5×	0.007	TP53
TP53 Regulates Transcription of Genes Involved in Cytochrome C Release	1	271.9×	0.007	TP53
TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain	1	259.6×	0.007	TP53
Regulation of TP53 Activity through Acetylation	1	228.4×	0.007	TP53
Pyroptosis	1	211.5×	0.008	TP53
Oncogene Induced Senescence	1	167.9×	0.010	TP53

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
thymocyte apoptotic process	2	1404.3×	6e-05	TP53, CHEK2
replicative senescence	2	991.3×	7e-05	TP53, CHEK2
cellular response to gamma radiation	2	601.9×	1e-04	TP53, CHEK2
intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	2	495.6×	1e-04	TP53, CHEK2
DNA damage response, signal transduction by p53 class mediator	2	358.6×	2e-04	TP53, CHEK2
cellular response to xenobiotic stimulus	2	240.7×	4e-04	TP53, CHEK2
double-strand break repair	2	203.0×	5e-04	TP53, CHEK2
negative regulation of helicase activity	1	8426.0×	0.001	TP53
cellular response to actinomycin D	1	8426.0×	0.001	TP53
regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1	8426.0×	0.001	TP53
negative regulation of G1 to G0 transition	1	8426.0×	0.001	TP53
positive regulation of mitochondrial membrane permeability	1	4213.0×	0.002	TP53
oligodendrocyte apoptotic process	1	4213.0×	0.002	TP53
negative regulation of glucose catabolic process to lactate via pyruvate	1	4213.0×	0.002	TP53
negative regulation of pentose-phosphate shunt	1	4213.0×	0.002	TP53
protein stabilization	2	66.9×	0.002	TP53, CHEK2
obsolete homolactic fermentation	1	2808.7×	0.002	TP53
signal transduction by p53 class mediator	1	2808.7×	0.002	TP53
negative regulation of miRNA processing	1	2808.7×	0.002	TP53
intrinsic apoptotic signaling pathway in response to hypoxia	1	2808.7×	0.002	TP53
negative regulation of DNA damage checkpoint	1	2808.7×	0.002	CHEK2
regulation of fibroblast apoptotic process	1	2808.7×	0.002	TP53
DNA damage response	2	53.5×	0.002	TP53, CHEK2
T cell proliferation involved in immune response	1	2106.5×	0.002	TP53
mitotic DNA damage checkpoint signaling	1	2106.5×	0.002	CHEK2
positive regulation of programmed necrotic cell death	1	2106.5×	0.002	TP53
oxidative stress-induced premature senescence	1	2106.5×	0.002	TP53
B cell lineage commitment	1	1685.2×	0.002	TP53
T cell lineage commitment	1	1685.2×	0.002	TP53
mRNA transcription	1	1685.2×	0.002	TP53

Therapeutics

Drugs indicated for this disease

1 approved, 5 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Mitotane	Approved (phase 4)
Cisplatin	Phase 3 (in late-stage trials)
Etoposide	Phase 3 (in late-stage trials)
Filgrastim	Phase 3 (in late-stage trials)
Linsitinib	Phase 3 (in late-stage trials)
Pegfilgrastim	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): ANTINEOPLASTON A10, Atezolizumab, Axitinib, Bevacizumab, Cabazitaxel, Cabozantinib, Camrelizumab, Dovitinib, Doxorubicin, Hydrocortisone, Lenvatinib, Megestrol Acetate, Milademetan, Nivolumab, Paclitaxel, Pembrolizumab, Sorafenib, Sunitinib, Tariquidar, Vincristine.

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TP53	NITROFURANTOIN
CHEK2	NERATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TP53	196	4
CHEK2	30	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53
FURAZOLIDONE	4	TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53
AMITRIPTYLINE HYDROCHLORIDE	4	TP53
ETHOPROPAZINE HYDROCHLORIDE	4	TP53
MECHLORETHAMINE HYDROCHLORIDE	4	TP53
ECONAZOLE NITRATE	4	TP53
TRIFLUPROMAZINE HYDROCHLORIDE	4	TP53
PROCHLORPERAZINE EDISYLATE	4	TP53
DEQUALINIUM CHLORIDE	4	TP53

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
CHEK2	690	Binding:687, Functional:2, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CHEK2	2.7.11.1	non-specific serine/threonine protein kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TP53	869
CHEK2	690

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Drug repurposing candidates

30 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Compound	Max phase	Cohort target (bioactivity)
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53
FURAZOLIDONE	4	TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53
AMITRIPTYLINE HYDROCHLORIDE	4	TP53
ETHOPROPAZINE HYDROCHLORIDE	4	TP53
MECHLORETHAMINE HYDROCHLORIDE	4	TP53
ECONAZOLE NITRATE	4	TP53
TRIFLUPROMAZINE HYDROCHLORIDE	4	TP53
PROCHLORPERAZINE EDISYLATE	4	TP53
DEQUALINIUM CHLORIDE	4	TP53

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	TP53, CHEK2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 86.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	40
Not specified	23
PHASE1	14
PHASE3	4
PHASE1/PHASE2	3
EARLY_PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00304070	PHASE3	COMPLETED	Cisplatin-Based Chemotherapy and/or Surgery in Treating Young Patients With Adrenocortical Tumor
NCT00777244	PHASE3	UNKNOWN	Efficacy of Adjuvant Mitotane Treatment (ADIUVO)
NCT00924989	PHASE3	COMPLETED	A Study of OSI-906 in Patients With Locally Advanced or Metastatic Adrenocortical Carcinoma
NCT03723941	PHASE3	COMPLETED	Adjuvant Chemotherapy vs. Observation/Mitotane After Primary Surgical Resection of Localized Adrenocortical CarcInoma
NCT02673333	PHASE2	ACTIVE_NOT_RECRUITING	Single Agent Pembrolizumab in Subjects With Advanced Adrenocortical Carcinoma
NCT02721732	PHASE2	ACTIVE_NOT_RECRUITING	Pembrolizumab in Treating Patients With Rare Tumors That Cannot Be Removed by Surgery or Are Metastatic
NCT02834013	PHASE2	ACTIVE_NOT_RECRUITING	Nivolumab and Ipilimumab in Treating Patients With Rare Tumors
NCT02867592	PHASE2	ACTIVE_NOT_RECRUITING	Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumors
NCT03127774	PHASE2	ACTIVE_NOT_RECRUITING	Surgery and Heated Intraperitoneal Chemotherapy for Adrenocortical Carcinoma
NCT03333616	PHASE2	ACTIVE_NOT_RECRUITING	Nivolumab Combined With Ipilimumab for Patients With Advanced Rare Genitourinary Tumors
NCT04318730	PHASE2	RECRUITING	Phase II Study for Combination of Camrelizumab and Apatinib in the Second-line Treatment of Recurrent or Metastatic Adrenocortical Carcinoma
NCT05036434	PHASE2	ACTIVE_NOT_RECRUITING	Phase II Trial of Pembrolizumab Plus Lenvatinib in Advanced Adrenal Cortical Carcinoma
NCT05286814	PHASE2	RECRUITING	PDS01ADC in Combination With Hepatic Artery Infusion Pump (HAIP) and Systemic Therapy for Subjects With Metastatic Colorectal Cancer, Intrahepatic Cholangiocarcinoma, or Metastatic Adrenocortical Carcinoma
NCT05563467	PHASE2	RECRUITING	Pembrolizumab in the Treatment of Advanced, Progressive Adrenocortical Carcinoma.
NCT05913427	PHASE2	RECRUITING	Evaluation of the Efficacy of Addition of Progesterone to Standard Chemotherapy in Adrenocortical Carcinoma (ACC)
NCT06006013	PHASE2	RECRUITING	Cabozantinib in Combination With Pembrolizumab for the Treatment of Patients With Locally Advanced, Metastatic, or Unresectable Adrenal Cortical Cancer
NCT06066333	PHASE2	RECRUITING	Study of Radiotherapy and Pembrolizumab in People With Adrenocortical Carcinoma
NCT06333314	PHASE2	RECRUITING	Dostarlimab for Locally Advanced or Metastatic Cancer (Non-colorectal/Non-endometrial) With Tumor dMMR/MSI
NCT06587802	PHASE2	RECRUITING	Phase II Study of PD-1 Antibody Combined With Radiotherapy in Recurrent or Metastatic Adrenal Cortical Carcinoma
NCT06831175	PHASE2	RECRUITING	Phase II Study of PD-1 Inhibitor Combined With Apatinib and Mitotane in the Treatment of Advanced Adrenal Cortical Carcinoma
NCT06900595	PHASE2	RECRUITING	Testing the Addition of an Anti-Cancer Drug, Cabozantinib to the Immunotherapy Drug Cemiplimab (REGN2810), in Adolescents and Adults With Advanced Adrenocortical Cancer
NCT07085572	PHASE2	RECRUITING	Cemiplimab as Maintenance Treatment for Advanced Adrenocortical Cancer
NCT00001339	PHASE2	COMPLETED	A Study of Combination Chemotherapy and Surgical Resection in the Treatment of Adrenocortical Carcinoma: Continuous Infusion Doxorubicin, Vincristine and Etoposide With Daily Mitotane Before and After Surgical Resection
NCT00002608	PHASE2	COMPLETED	Combination Chemotherapy and Tamoxifen in Treating Patients With Solid Tumors
NCT00002921	PHASE2	TERMINATED	S9427, Suramin in Treating Patients With Stage III or Stage IV Adrenocortical Cancer Incurable by Surgery
NCT00003453	PHASE2	TERMINATED	Antineoplaston Therapy in Treating Patients With Stage IV Adrenal Gland Cancer
NCT00091182	PHASE2	COMPLETED	Oxaliplatin in Treating Young Patients With Recurrent Solid Tumors That Have Not Responded to Previous Treatment
NCT00324012	PHASE2	COMPLETED	Trial With Taxotere and Cisplatin in Non-operable Adrenocortical Carcinoma
NCT00453895	PHASE2	COMPLETED	Sunitinib in Refractory Adrenocortical Carcinoma
NCT00454103	PHASE1/PHASE2	COMPLETED	Evaluation of 123I-Iodometomidate for Adrenal Scintigraphy
NCT00469469	PHASE2	WITHDRAWN	Treatment Study Using Bevacizumab for Patients With Adrenocortical Carcinoma
NCT00778817	PHASE2	TERMINATED	IMC-A12 With Mitotane vs Mitotane Alone in Recurrent, Metastatic, or Primary ACC That Cannot Be Removed by Surgery
NCT00786110	PHASE2	UNKNOWN	Sorafenib Plus Paclitaxel in Adreno-Cortical-Cancer Patients
NCT00831844	PHASE2	COMPLETED	Cixutumumab in Treating Patients With Relapsed or Refractory Solid Tumors
NCT00848016	PHASE2	COMPLETED	Gossypol Acetic Acid in Treating Patients With Recurrent, Metastatic, or Primary Adrenocortical Cancer That Cannot Be Removed By Surgery
NCT01262235	PHASE1/PHASE2	COMPLETED	A Dose Finding Study of TKM-080301 Infusion in Neuroendocrine Tumors (NET) and Adrenocortical Carcinoma (ACC) Patients
NCT01514526	PHASE2	COMPLETED	Clinical Trial of Dovitinib in First-line Metastatic or Locally Advanced Non-resectable Adrenocortical Carcinoma
NCT01678105	PHASE2	COMPLETED	A Phase II Study of Dovitinib in Recurrent and/or Metastatic Adenoid Cystic Carcinoma of the Salivary Glands
NCT01833832	PHASE2	COMPLETED	Surgery and Heated Chemotherapy for Adrenocortical Carcinoma
NCT02720484	PHASE2	TERMINATED	Nivolumab in Treating Patients With Metastatic Adrenocortical Cancer

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CABOZANTINIB	4	6
MITOTANE	4	6
CISPLATIN	4	5
SODIUM THIOSULFATE	4	2
CABAZITAXEL	4	1
DOSTARLIMAB	4	1
FLOXURIDINE	4	1
PEGFILGRASTIM	4	1
SUNITINIB	4	1
SURAMIN	3	4
DOVITINIB	3	2
LINSITINIB	3	1
MILADEMETAN	3	1
CIXUTUMUMAB	2	2
TIGOZERTINIB	2	1
IODOMETOMIDATE I-123, R-	1	1
CHEMBL1572655	0	6
CHEMBL4578973	0	2
CHEMBL3753202	0	2
CHEMBL4215501	0	2
CHEMBL4849721	0	2
EXELIXIS	0	2
CHEMBL275117	0	1
CHEMBL4517714	0	1
CHEMBL5405436	0	1