Volasertib

Summary

Volasertib (CHEMBL1233528) is a phase-3 clinical-stage small-molecule antineoplastic agent targeting PLK1; indicated across 11 conditions including acute myeloid leukemia and myelodysplastic syndrome; with CIViC clinical evidence for 1 variant-indication association (e.g. RB1 Loss-of-function in triple-receptor negative breast cancer).

At a glance

• Status: Max clinical phase 3 (not approved)
• Modality: Small molecule
• Targets: 1 (PLK1)
• Indications: 11 conditions
• Clinical trials: 25
• Precision-oncology evidence (CIViC): 1 variant–indication association
• Chemistry: 618.8 Da · C34H50N8O3

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL1233528
Name	Volasertib
Type	Small molecule
Max phase	3
FDA approved	no
PubChem CID	10461508
ChEBI	CHEBI:231358
Molecular formula	C34H50N8O3
Molecular weight	618.8
InChIKey	SXNJFOWDRLKDSF-XKHVUIRMSA-N

SMILES: CC[C@@H]1C(=O)N(C2=CN=C(N=C2N1C(C)C)NC3=C(C=C(C=C3)C(=O)NC4CCC(CC4)N5CCN(CC5)CC6CC6)OC)C

IUPAC name: N-[4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-4-[[(7R)-7-ethyl-5-methyl-6-oxo-8-propan-2-yl-7H-pteridin-2-yl]amino]-3-methoxybenzamide

ChEBI definition: A member of the class of pteridines that is (7R)-7-ethyl-5-methyl-8-(propan-2-yl)-7,8-dihydropteridin-6(5H)-one substituted by a [4-({trans-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl}carbamoyl)-2-methoxyphenyl]amino group at position 2. It is as polo-like kinase 1 inhibitor (IC50 = 0.87 nM) with potential antineoplastic activity.

Pharmacological roles (ChEBI): antineoplastic agent, apoptosis inducer, EC 2.7.11.21 (polo kinase) inhibitor.

Also known as: BI 6727, Bi-6727, BI-6727, BI6727, Volasertib, VOLASERTIB, BI6727 (VOLASERTIB), BI6727 (Volasertib)

Parent form; salt/anhydrous children: CHEMBL2105742

Patent coverage: 554 distinct patent families (1,511 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 1,386 (92%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).

Gene	Target	Action	pAffinity	Cancer dependency	UniProt
PLK1	polo like kinase 1	Inhibition	9.06	99.9% (common-essential)	P53350

Broader ChEMBL bioactivity targets: 10 (assay-derived). Sample: Pyridoxal kinase, Bromodomain-containing protein 4, Bromodomain testis-specific protein, Focal adhesion kinase 1, Serine/threonine-protein kinase PLK1, Serine/threonine-protein kinase PLK3, Calcium/calmodulin-dependent protein kinase kinase 2, Wee1-like protein kinase, Serine/threonine-protein kinase Nek3, Serine/threonine-protein kinase PLK2.

Bioactivity

ChEMBL activities: 43 potent at pChembl ≥ 5 of 43 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
PLK1	9.09	IC50	0.82	nM	CHEMBL_ACT_25521590
PLK1	9.06	IC50	0.87	nM	CHEMBL_ACT_12195466
PLK1	9.06	IC50	0.87	nM	CHEMBL_ACT_16742605
PLK1	9.06	IC50	0.87	nM	CHEMBL_ACT_16844149
PLK1	9.06	IC50	0.87	nM	CHEMBL_ACT_20690276
PLK1	9.06	IC50	0.87	nM	CHEMBL_ACT_24954250
PLK1	9.06	IC50	0.87	nM	CHEMBL_ACT_25613244
PLK1	9.06	IC50	0.87	nM	CHEMBL_ACT_26023218
PLK1	9.06	IC50	0.87	nM	CHEMBL_ACT_26239302
PLK1	9.06	IC50	0.87	nM	CHEMBL_ACT_26277413
PLK1	9.06	IC50	0.87	nM	CHEMBL_ACT_29153346
PLK1	9.06	IC50	0.87	nM	CHEMBL_ACT_29178151
PLK1	8.63	IC50	2.36	nM	CHEMBL_ACT_22985337
PLK1	8.6	IC50	2.5	nM	CHEMBL_ACT_25097350
PLK2	8.3	IC50	5	nM	CHEMBL_ACT_24954251
PLK2	8.3	IC50	5	nM	CHEMBL_ACT_26239301
PLK2	8.3	IC50	5	nM	CHEMBL_ACT_26277416
PLK1	7.96	EC50	11	nM	CHEMBL_ACT_24953785
PLK2	7.96	EC50	11	nM	CHEMBL_ACT_24953786
PLK3	7.96	EC50	11	nM	CHEMBL_ACT_24953787
PLK3	7.25	IC50	56	nM	CHEMBL_ACT_24954252
PLK3	7.25	IC50	56	nM	CHEMBL_ACT_26239303
PLK3	7.25	IC50	56	nM	CHEMBL_ACT_26277419
BRD4	7.11	Kd	77	nM	CHEMBL_ACT_24343370
BRD4	7.1	Kd	79	nM	CHEMBL_ACT_16844142
BRD4	7.1	Kd	79	nM	CHEMBL_ACT_24958521
BRD4	7.1	Kd	79	nM	CHEMBL_ACT_26023219
BRDT	6.95	Kd	113	nM	CHEMBL_ACT_24343401
BRD4	6.92	IC50	119.8	nM	CHEMBL_ACT_25521641
BRD4	6.77	Kd	169	nM	CHEMBL_ACT_24343363

Target pathways

Aggregated over 1 target gene(s): PLK1.

Top Reactome pathways

25 total, by targets touching each:

Pathway	Targets	Genes
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	1	PLK1
Polo-like kinase mediated events	1	PLK1
Golgi Cisternae Pericentriolar Stack Reorganization	1	PLK1
APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1	1	PLK1
Phosphorylation of the APC/C	1	PLK1
Phosphorylation of Emi1	1	PLK1
Condensation of Prophase Chromosomes	1	PLK1
Separation of Sister Chromatids	1	PLK1
Resolution of Sister Chromatid Cohesion	1	PLK1
Regulation of PLK1 Activity at G2/M Transition	1	PLK1
Activation of NIMA Kinases NEK9, NEK6, NEK7	1	PLK1
Loss of Nlp from mitotic centrosomes	1	PLK1
Recruitment of mitotic centrosome proteins and complexes	1	PLK1
Loss of proteins required for interphase microtubule organization from the centrosome	1	PLK1
Recruitment of NuMA to mitotic centrosomes	1	PLK1
Anchoring of the basal body to the plasma membrane	1	PLK1
RHO GTPases Activate Formins	1	PLK1
Mitotic Prometaphase	1	PLK1
Mitotic Metaphase/Anaphase Transition	1	PLK1
Mitotic Telophase/Cytokinesis	1	PLK1
Cyclin A/B1/B2 associated events during G2/M transition	1	PLK1
The role of GTSE1 in G2/M progression after G2 checkpoint	1	PLK1
AURKA Activation by TPX2	1	PLK1
EML4 and NUDC in mitotic spindle formation	1	PLK1
Regulation of MITF-M-dependent genes involved in cell cycle and proliferation	1	PLK1

Dominant GO biological processes

GO term	Targets
mitotic sister chromatid segregation	1
G2/M transition of mitotic cell cycle	1
negative regulation of transcription by RNA polymerase II	1
mitotic cell cycle	1
mitotic cytokinesis	1
microtubule bundle formation	1
double-strand break repair	1
protein phosphorylation	1
mitotic spindle organization	1
sister chromatid cohesion	1
mitotic chromosome condensation	1
mitotic nuclear membrane disassembly	1
metaphase/anaphase transition of mitotic cell cycle	1
mitotic spindle assembly checkpoint signaling	1
mitotic G2 DNA damage checkpoint signaling	1

Indications & clinical

Indications

11 indications (0 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).

Indication	Trial phase	MONDO	EFO
acute myeloid leukemia	3	MONDO:0018874	EFO:0000222
myelodysplastic syndrome	2	MONDO:0018881	EFO:0000198
neoplasm	2	MONDO:0005070	EFO:0000616
ovarian neoplasm	2	MONDO:0021068	EFO:0003893
non-small cell lung carcinoma	2	MONDO:0005233	EFO:0003060
leukemia	1	MONDO:0005059	EFO:0000565
acute monocytic leukemia	1	MONDO:0007896	EFO:0000221
lymphoma	1	MONDO:0005062	EFO:0000574
primary cutaneous T-cell non-Hodgkin lymphoma	1	MONDO:0000607	EFO:0002913
acute erythroid leukemia	1	MONDO:0017858	EFO:1001257
mature T-cell and NK-cell non-Hodgkin lymphoma	1	MONDO:0000430	MONDO:0000430

Clinical trials

Total trials: 25.

Phase distribution

Phase	Trials
PHASE1	19
PHASE2	5
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01721876	PHASE3	COMPLETED	Volasertib in Combination With Low-dose Cytarabine in Patients Aged 65 Years and Above With Previously Untreated Acute Myeloid Leukaemia, Who Are Ineligible for Intensive Remission Induction Therapy (POLO-AML-2)
NCT00804856	PHASE2	COMPLETED	Phase I/IIa Trial to Investigate BI 6727 (Volasertib) as Monotherapy or in Combination With Cytarabine in Acute Myeloid Leukaemia
NCT00824408	PHASE2	COMPLETED	Trial of BI 6727 (Volasertib) Monotherapy and BI 6727 in Combination With Pemetrexed Compared to Pemetrexed Monotherapy in Advanced NSCLC
NCT01023958	PHASE2	COMPLETED	Intravenous BI 6727 (Volasertib) in 2nd Line Treatment of Urothelial Cancer
NCT01121406	PHASE2	COMPLETED	BI 6727 (Volasertib) Randomised Trial in Ovarian Cancer
NCT02198482	PHASE2	TERMINATED	Trial of Intensive Chemotherapy With or Without Volasertib in Patients With Newly Diagnosed High-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)
NCT00969553	PHASE1	COMPLETED	Dose Finding Study of BI 6727 (Volasertib) in Patients With Various Solid Cancers
NCT00969761	PHASE1	COMPLETED	BI 6727 (Volasertib) in Combination With Cisplatin or Carboplatin in Patients With Advanced or Metastatic Solid Tumour
NCT01022853	PHASE1	COMPLETED	Combination of BI6727 (Volasertib) and BIBF1120 in Solid Tumors
NCT01145885	PHASE1	COMPLETED	BI 6727 (Volasertib) Human ADME Trial in Various Solid Tumours
NCT01206816	PHASE1	COMPLETED	An Open Label Phase I Dose Escalation Trial of Intravenous BI 6727 (Volasertib)in Combination With Oral BIBW 2992 (Afatinib) in Patients With Advanced Solid Tumours
NCT01348347	PHASE1	COMPLETED	BI 6727 (Volasertib) Monotherapy Phase I Trial in Japanese Patients With Advanced Solid Tumours
NCT01662505	PHASE1	COMPLETED	Volasertib in Japanese Patients With Acute Myeloid Leukemia (AML)
NCT01772563	PHASE1	COMPLETED	Investigation of Potential Drug-drug Interaction of Volasertib With Itraconazole in Patients With Various Tumours
NCT01957644	PHASE1	TERMINATED	Phase I Dose Escalation Trial of Volasertib in Combination With Azacitidine in Patients With MDS or CMML
NCT01971476	PHASE1	COMPLETED	Open Dose Escalating Trial to Determine the Maximum Tolerated Dose in Paediatric Patients With Advanced Cancers for Whom no Therapy is Known
NCT02201329	PHASE1	COMPLETED	Volasertib in Combination With Azacitidine in Japanese Patients With Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia
NCT02273388	PHASE1	COMPLETED	BI 6727 Administered Intravenously Every 3 Weeks in Patients With Solid Tumours
NCT02527174	PHASE1	WITHDRAWN	A Study of Volasertib Plus Induction Chemotherapy for Acute Myeloid Leukemia
NCT02721875	PHASE1	TERMINATED	Trial of Volasertib With or Without Azacitidine in Patients With Myelodysplastic Syndromes
NCT02722135	PHASE1	WITHDRAWN	A Study to Find a Safe Dose of Volasertib Given in Addition to Standard Salvage Chemotherapy in Children (Age 3 Months to Less Than 18 Years) With Acute Myeloid Leukaemia, in Whom Front-line Chemotherapy Failed
NCT02757248	PHASE1	WITHDRAWN	Ph1 Volasertib Plus Romidepsin in R/R PTCL and CTCL
NCT02861040	PHASE1	WITHDRAWN	Volasertib and Vincristine Sulfate Liposome in Treating Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia
NCT02875002	PHASE1	WITHDRAWN	Study of Volasertib and Belinostat in Patients With Relapsed and Refractory Aggressive B-cell and T-cell Lymphomas
NCT02905994	PHASE1	WITHDRAWN	Volasertib Combined With Induction Chemotherapy in Acute Myeloid Leukemia

Clinical evidence (CIViC)

Variant × indication × effect (1 predictive associations from 1 curated evidence items):

Variant	Indication	Effect	Therapy	Level	CIViC
RB1 Loss-of-function	Triple-receptor Negative Breast Cancer	Sensitivity/Response	Volasertib	CIViC D	EID12331

Pharmacology

Pharmacogenomics

No PharmGKB pharmacogenomic data curated for this drug.

Related molecules

Related molecules

Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.

30 molecules share ≥1 primary target. Top 30 by shared-target count:

Molecule	Source	Status	Shared targets
BOSUTINIB	ChEMBL	Phase 4 (approved)	PLK1
BRIGATINIB	ChEMBL	Phase 4 (approved)	PLK1
FEDRATINIB	ChEMBL	Phase 4 (approved)	PLK1
RUXOLITINIB	ChEMBL	Phase 4 (approved)	PLK1
VORINOSTAT	ChEMBL	Phase 4 (approved)	PLK1
LESTAURTINIB	ChEMBL	Phase 3	PLK1
QUERCETIN	ChEMBL	Phase 3	PLK1
RIGOSERTIB	ChEMBL	Phase 3	PLK1
ADAVOSERTIB	ChEMBL	Phase 2	PLK1
AZD-6482	ChEMBL	Phase 2	PLK1
BAICALEIN	ChEMBL	Phase 2	PLK1
BI-2536	ChEMBL	Phase 2	PLK1
DANUSERTIB	ChEMBL	Phase 2	PLK1
ELLAGIC ACID	ChEMBL	Phase 2	PLK1
ONVANSERTIB	ChEMBL	Phase 2	PLK1
R-406	ChEMBL	Phase 2	PLK1
SILMITASERTIB	ChEMBL	Phase 2	PLK1
SOTRASTAURIN	ChEMBL	Phase 2	PLK1
THYMOQUINONE	ChEMBL	Phase 2	PLK1
Afatinib	PubChem	Approved	PLK1
Binimetinib	PubChem	Approved	PLK1
Crizotinib	PubChem	Approved	PLK1
Fostamatinib	PubChem	Approved	PLK1
Gefitinib	PubChem	Approved	PLK1
Idelalisib	PubChem	Approved	PLK1
Imatinib	PubChem	Approved	PLK1
Pazopanib	PubChem	Approved	PLK1
regorafenib	PubChem	Approved	PLK1
Selumetinib	PubChem	Approved	PLK1
Trametinib	PubChem	Approved	PLK1