Dordaviprone

Summary

Dordaviprone (CHEMBL4297310) is a phase-3 clinical-stage small-molecule antineoplastic agent targeting CLPP; indicated across 13 conditions including paraganglioma and glioblastoma; with CIViC clinical evidence for 3 variant-indication associations (e.g. H3-3A K28M in diffuse midline glioma, h3 k27-altered).

At a glance

• Status: Max clinical phase 3 (not approved)
• Modality: Small molecule
• Targets: 1 (CLPP)
• Indications: 13 conditions
• Clinical trials: 23
• Precision-oncology evidence (CIViC): 3 variant–indication associations
• Chemistry: 386.5 Da · C24H26N4O

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL4297310
Name	Dordaviprone
Type	Small molecule
Max phase	3
FDA approved	no
PubChem CID	73777259
ChEBI	CHEBI:232328
Molecular formula	C24H26N4O
Molecular weight	386.5
InChIKey	VLULRUCCHYVXOH-UHFFFAOYSA-N

SMILES: CC1=CC=CC=C1CN2C(=O)C3=C(CCN(C3)CC4=CC=CC=C4)N5C2=NCC5

IUPAC name: 11-benzyl-7-[(2-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one

ChEBI definition: An organic heterotricyclic compound that is 2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one substituted by 2-methylbenzyl and benzyl groups at positions 4 and 7, respectively. It is a selective antagonist of the dopamine receptor D2 and an allosteric agonist of mitochondrial protease caseinolytic protease P.

Pharmacological roles (ChEBI): antineoplastic agent, dopamine receptor D2 antagonist, apoptosis inducer.

Also known as: Dordaviprona, Dordaviprone, NSC-350625, Onc 201, Onc-201, Onc201, ONC201, TIC-10, TIC10, DORDAVIPRONE, TIC10 ANGULAR

Parent form; salt/anhydrous children: CHEMBL5184009, CHEMBL5563117, CHEMBL6068398

Patent coverage: 329 distinct patent families (819 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 680 (83%) 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
CLPP	caseinolytic mitochondrial matrix peptidase proteolytic subunit	Activation		4.1%	Q16740

Broader ChEMBL bioactivity targets: 7 (assay-derived). Sample: D(2) dopamine receptor, D(3) dopamine receptor, Voltage-gated inwardly rectifying potassium channel KCNH2, Cytochrome P450 2D6, Probable G-protein coupled receptor 132, Cytochrome P450 3A4, ATP-dependent Clp protease proteolytic subunit, mitochondrial.

Bioactivity

ChEMBL activities: 12 potent at pChembl ≥ 5 of 17 total. Top 100 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
CLPP	7.92	EC50	12.02	nM	CHEMBL_ACT_25927941
CLPP	6	EC50	1000	nM	CHEMBL_ACT_24925752
CLPP	5.83	EC50	1490	nM	CHEMBL_ACT_25985634
CLPP	5.76	EC50	1720	nM	CHEMBL_ACT_26049221
CLPP	5.76	EC50	1720	nM	CHEMBL_ACT_29316715
CLPP	5.62	EC50	2400	nM	CHEMBL_ACT_25985506
KCNH2	5.43	IC50	3710	nM	CHEMBL_ACT_24925874
KCNH2	5.43	IC50	3710	nM	CHEMBL_ACT_29284961
DRD3	5.39	Ki	4090	nM	CHEMBL_ACT_29161268
CLPP	5.38	EC50	4130	nM	CHEMBL_ACT_25985638
CLPP	5.23	EC50	5900	nM	CHEMBL_ACT_29161231
CYP2D6	5.11	IC50	7730	nM	CHEMBL_ACT_24925867

Target pathways

Aggregated over 1 target gene(s): CLPP.

Top Reactome pathways

1 total, by targets touching each:

Pathway	Targets	Genes
Mitochondrial protein degradation	1	CLPP

Dominant GO biological processes

GO term	Targets
proteolysis	1
protein quality control for misfolded or incompletely synthesized proteins	1
membrane protein proteolysis	1
mitochondrial protein catabolic process	1
obsolete proteolysis involved in protein catabolic process	1

Indications & clinical

Indications

13 diseases in clinical trials (phase 1–3, investigational — not approved indications). Highest ChEMBL trial phase per disease; a non-cancer approved use is occasionally logged at phase 3 here.

Disease (in trials)	Phase	MONDO	EFO
paraganglioma	3	MONDO:0000448	EFO:1000453
glioblastoma	2	MONDO:0018177	EFO:0000519
neuroendocrine neoplasm	2	MONDO:0019496	EFO:1001901
breast neoplasm	2	MONDO:0021100	MONDO:0007254
endometrium neoplasm	2	MONDO:0021251	MONDO:0011962
plasma cell myeloma	1	MONDO:0009693	EFO:0001378
neoplasm	1	MONDO:0005070	EFO:0000616
diffuse intrinsic pontine glioma	1	MONDO:0006033	EFO:1000026
gliosarcoma	1	MONDO:0016681	EFO:1001465
myelodysplastic syndrome	1	MONDO:0018881	EFO:0000198
acute lymphoblastic leukemia	1	MONDO:0004967	EFO:0000220
acute myeloid leukemia	1	MONDO:0018874	EFO:0000222
meningioma	1	MONDO:0016642	MONDO:0016642

Clinical trials

Total trials: 23.

Phase distribution

Phase	Trials
PHASE2	9
PHASE1	6
PHASE1/PHASE2	3
Not specified	3
PHASE3	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05476939	PHASE3	RECRUITING	Biological Medicine for Diffuse Intrinsic Pontine Glioma (DIPG) Eradication 2.0
NCT05580562	PHASE3	RECRUITING	ONC201 in H3 K27M-mutant Diffuse Glioma Following Radiotherapy (the ACTION Study)
NCT05009992	PHASE2	RECRUITING	Combination Therapy for the Treatment of Diffuse Midline Gliomas
NCT02038699	PHASE1/PHASE2	WITHDRAWN	A First-in-man Phase I/II Study of Oral ONC201 in Patients With Advanced Cancer
NCT02525692	PHASE2	TERMINATED	Oral ONC201 in Adult Recurrent Glioblastoma
NCT02863991	PHASE1/PHASE2	TERMINATED	Oral ONC201 in Relapsed/Refractory Multiple Myeloma
NCT03034200	PHASE2	COMPLETED	Phase 2 Study of ONC201 in Neuroendocrine Tumors
NCT03099499	PHASE2	TERMINATED	Single Agent ONC201 in Recurrent or Metastatic Endometrial Cancer
NCT03295396	PHASE2	TERMINATED	ONC201 in Adults With Recurrent H3 K27M-mutant Glioma
NCT03394027	PHASE2	COMPLETED	ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma
NCT03485729	PHASE2	TERMINATED	ONC201 in Recurrent or Metastatic Type II Endometrial Cancer Endometrial Cancer
NCT03492138	PHASE1/PHASE2	TERMINATED	Ixazomib, ONC201, and Dexamethasone in Relapsed/Refractory Multiple Myeloma
NCT04629209	PHASE2	WITHDRAWN	A Phase II, Open Label Study of ONC201 in Adults With EGFR-low Glioblastoma
NCT06012929	PHASE2	WITHDRAWN	A Study of ONC201 for Refractory Meningioma
NCT05542407	PHASE1	RECRUITING	ONC201 and Atezolizumab in Obesity-Driven Endometrial Cancer
NCT02250781	PHASE1	COMPLETED	Oral ONC201 in Treating Patients With Advanced Solid Tumors
NCT02324621	PHASE1	COMPLETED	Continuation of Oral ONC201 in Treating Patients With Advanced Solid Tumors
NCT02609230	PHASE1	COMPLETED	A Dose-Escalation Study of Onc201 Administered Every One or Three Weeks in Advanced Solid Tumors and Multiple Myeloma
NCT03416530	PHASE1	TERMINATED	ONC201 in Pediatric H3 K27M Gliomas
NCT03932643	PHASE1	COMPLETED	ONC-201 Maintenance Therapy in Acute Myeloid Leukemia and Myelodysplastic Syndrome After Stem Cell Transplant
NCT03134131	Not specified	NO_LONGER_AVAILABLE	Expanded Access to ONC201 for Patients With H3 K27M-mutant and/or Midline High Grade Gliomas
NCT04617002	Not specified	APPROVED_FOR_MARKETING	Intermediate-size Expanded Access to ONC201 for Patients With H3 K27M-mutant and/or Midline Gliomas
NCT05392374	Not specified	NO_LONGER_AVAILABLE	Expanded Access Use of ONC201 in a Patient With Diffuse Intrinsic Pontine Gliomas

Clinical evidence (CIViC)

Variant × indication × effect (3 predictive associations from 3 curated evidence items):

Variant	Indication	Effect	Therapy	Level	CIViC
H3-3A K28M	Diffuse Midline Glioma, H3 K27-altered	Sensitivity/Response	Dordaviprone	CIViC A	EID12695
DRD5 low expression	Glioblastoma	Sensitivity/Response	Dordaviprone	CIViC B	EID7600
H3-3A K28M	Glioma	Sensitivity/Response	Dordaviprone	CIViC B	EID7601

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline or drug-level clinical/variant annotations in PharmGKB for this molecule.

Related molecules

Related molecules

No competitor molecules sharing a primary target (ChEMBL phase ≥2 or PubChem drug-class).