Crenolanib

Summary

Crenolanib (CHEMBL2105728) is a phase-3 clinical-stage small-molecule EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor targeting PDGFRA, PDGFRB, and KIT; indicated across 6 conditions including acute myeloid leukemia and gastrointestinal stromal tumor; with CIViC clinical evidence for 20 variant-indication associations (e.g. FLT3 Y572C in acute myeloid leukemia).

At a glance

• Status: Max clinical phase 3 (not approved)
• Modality: Small molecule
• Targets: 5 (PDGFRA, PDGFRB, KIT…)
• Indications: 6 conditions
• Clinical trials: 14
• Precision-oncology evidence (CIViC): 20 variant–indication associations
• Chemistry: 443.5 Da · C26H29N5O2

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL2105728
Name	Crenolanib
Type	Small molecule
Max phase	3
FDA approved	no
PubChem CID	10366136
ChEBI	CHEBI:145365
Molecular formula	C26H29N5O2
Molecular weight	443.5
InChIKey	DYNHJHQFHQTFTP-UHFFFAOYSA-N

SMILES: CC1(COC1)COC2=CC3=C(C=C2)N(C=N3)C4=NC5=C(C=CC=C5N6CCC(CC6)N)C=C4

IUPAC name: 1-[2-[5-[(3-methyloxetan-3-yl)methoxy]benzimidazol-1-yl]quinolin-8-yl]piperidin-4-amine

ChEBI definition: A member of the class of benzimidazoles that is 1H-benzimidazole which is substituted by a 8-(4-aminopiperidin-1-yl)quinolin-2-yl group at position 1 and by a (3-methyloxetan-3-yl)methoxy group at position 5. It is an inhibitor of type III tyrosine kinases, PDGFRα/β and FLT3 (IC50 of 11, 3.2, and 4 nM). Currently under clinical development for the treatment of acute myeloid leukemia.

Pharmacological roles (ChEBI): EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor, angiogenesis inhibitor, antineoplastic agent, apoptosis inducer.

Also known as: ARO 002, ARO-002, CP 868596, CP-868,596, CP-868596, Crenolanib, CRENOLANIB, CRENOLANIB (CP-868596), Crenolanib (CP-868596)

Parent form; salt/anhydrous children: CHEMBL2146086

Patent coverage: 877 distinct patent families (2,167 SureChEMBL compound mentions), from 4 matched compound structure(s). One matched structure accounts for 2,048 (95%) 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
PDGFRA	platelet derived growth factor receptor alpha	Inhibition	8.68	6.2%	P16234
PDGFRB	platelet derived growth factor receptor beta	Inhibition	8.49	2.3%	P09619
KIT	KIT proto-oncogene, receptor tyrosine kinase	Inhibition	7.11	0.5%	P10721
CSF1R	colony stimulating factor 1 receptor	Inhibition	7.52	0%	P07333
FLT3	fms related receptor tyrosine kinase 3	Inhibition	9.13	0.9%	P36888

Broader ChEMBL bioactivity targets: 64 (assay-derived). Sample: Platelet-derived growth factor receptor beta, Receptor-type tyrosine-protein kinase FLT3, Platelet-derived growth factor receptor alpha, Proto-oncogene tyrosine-protein kinase receptor Ret, Platelet-derived growth factor receptor, Dual specificity tyrosine-phosphorylation-regulated kinase 1A, Phosphorylase b kinase gamma catalytic chain, liver/testis isoform, 5’-AMP-activated protein kinase subunit gamma-1, 5’-AMP-activated protein kinase subunit gamma-2, Tyrosine-protein kinase Lck.

Bioactivity

ChEMBL activities: 98 potent at pChembl ≥ 5 of 100 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
FLT3	10.8	Kd	0.02	nM	CHEMBL_ACT_28884566
FLT3	10.22	IC50	0.06	nM	CHEMBL_ACT_19067258
FLT3	10.22	IC50	0.06	nM	CHEMBL_ACT_24992777
FLT3	9.82	Kd	0.15	nM	CHEMBL_ACT_19250424
FLT3	9.8	Kd	0.16	nM	CHEMBL_ACT_19250400
FLT3	9.72	Kd	0.19	nM	CHEMBL_ACT_28884581
FLT3	9.7	Kd	0.2	nM	CHEMBL_ACT_28884536
FLT3	9.7	Kd	0.2	nM	CHEMBL_ACT_28884551
FLT3	9.59	Kd	0.26	nM	CHEMBL_ACT_19250406
FLT3	9.54	IC50	0.29	nM	CHEMBL_ACT_24992756
FLT3	9.52	IC50	0.3	nM	CHEMBL_ACT_19067259
FLT3	9.52	IC50	0.3	nM	CHEMBL_ACT_24992776
FLT3	9.41	Kd	0.39	nM	CHEMBL_ACT_28884656
FLT3	9.09	Kd	0.82	nM	CHEMBL_ACT_28884641
FLT3	8.89	IC50	1.3	nM	CHEMBL_ACT_22960941
FLT3	8.89	IC50	1.3	nM	CHEMBL_ACT_24797160
FLT3	8.89	IC50	1.3	nM	CHEMBL_ACT_26122118
FLT3	8.89	Kd	1.3	nM	CHEMBL_ACT_28884671
SIK3	8.7	Kd	2	nM	CHEMBL_ACT_17938174
FLT3	8.7	IC50	2	nM	CHEMBL_ACT_24797156
FLT3	8.7	IC50	2	nM	CHEMBL_ACT_24992771
FLT3	8.7	IC50	2	nM	CHEMBL_ACT_26122121
FLT3	8.52	IC50	3	nM	CHEMBL_ACT_16609128
CMPK1	8.52	Kd	3	nM	CHEMBL_ACT_17893026
FLT3	8.4	IC50	4	nM	CHEMBL_ACT_16609132
FLT3	8.16	IC50	6.9	nM	CHEMBL_ACT_24797146
FLT3	8.16	IC50	6.9	nM	CHEMBL_ACT_26122120
OLA1	8.15	Kd	7	nM	CHEMBL_ACT_17922930
SUCLA2	8.15	Kd	7	nM	CHEMBL_ACT_17942579
NTRK1	8.1	Kd	8	nM	CHEMBL_ACT_17922532

Target pathways

Aggregated over 5 target gene(s): PDGFRA, PDGFRB, KIT, CSF1R, FLT3.

Top Reactome pathways

74 total, by targets touching each:

Pathway	Targets	Genes
PIP3 activates AKT signaling	4	FLT3, KIT, PDGFRA, PDGFRB
Constitutive Signaling by Aberrant PI3K in Cancer	4	FLT3, KIT, PDGFRA, PDGFRB
RAF/MAP kinase cascade	4	FLT3, KIT, PDGFRA, PDGFRB
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	4	FLT3, KIT, PDGFRA, PDGFRB
Downstream signal transduction	2	PDGFRA, PDGFRB
Signaling by PDGF	2	PDGFRA, PDGFRB
PI3K Cascade	1	FLT3
Developmental Biology	1	KIT
Signaling by SCF-KIT	1	KIT
Regulation of KIT signaling	1	KIT
Signal Transduction	1	KIT
Disease	1	KIT
Negative regulation of the PI3K/AKT network	1	KIT
Generic Transcription Pathway	1	KIT
PI3K/AKT Signaling in Cancer	1	KIT
Other interleukin signaling	1	CSF1R
Diseases of signal transduction by growth factor receptors and second messengers	1	KIT
MAPK family signaling cascades	1	KIT
MAPK1/MAPK3 signaling	1	KIT
RNA Polymerase II Transcription	1	KIT
Gene expression (Transcription)	1	KIT
Transcriptional Regulation by VENTX	1	CSF1R
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1	KIT
TFAP2 (AP-2) family regulates transcription of growth factors and their receptors	1	KIT
Intracellular signaling by second messengers	1	KIT
Signaling by Receptor Tyrosine Kinases	1	KIT
FLT3 Signaling	1	FLT3
STAT5 Activation	1	FLT3
Dasatinib-resistant KIT mutants	1	KIT
Imatinib-resistant KIT mutants	1	KIT

Dominant GO biological processes

GO term	Targets
cell surface receptor protein tyrosine kinase signaling pathway	5
positive regulation of cell population proliferation	5
cell migration	5
protein autophosphorylation	5
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	5
protein phosphorylation	5
peptidyl-tyrosine phosphorylation	4
positive regulation of cell migration	4
regulation of actin cytoskeleton organization	3
cell chemotaxis	3
positive regulation of ERK1 and ERK2 cascade	3
chemotaxis	3
signal transduction	3
cytokine-mediated signaling pathway	3
hemopoiesis	3

Indications & clinical

Indications

6 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
gastrointestinal stromal tumor	3	MONDO:0011719	MONDO:0011719
glioblastoma	2	MONDO:0018177	EFO:0000519
paraganglioma	2	MONDO:0000448	EFO:1000453
gastric adenocarcinoma	1	MONDO:0005036	EFO:0000503
diffuse intrinsic pontine glioma	1	MONDO:0006033	EFO:1000026

Clinical trials

Total trials: 14.

Phase distribution

Phase	Trials
PHASE2	5
PHASE3	4
PHASE1	4
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02298166	PHASE3	TERMINATED	Study of Crenolanib in Combination With Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia and Activating FLT3 Mutations
NCT02847429	PHASE3	UNKNOWN	Randomized Trial of Crenolanib in Subjects With D842V Mutated GIST
NCT03250338	PHASE3	COMPLETED	Study Investigating the Efficacy of Crenolanib With Chemotherapy vs Chemotherapy Alone in R/R FLT3 Mutated AML
NCT03258931	PHASE3	COMPLETED	Study of Crenolanib vs Midostaurin Following Induction Chemotherapy and Consolidation Therapy in Newly Diagnosed FLT3 Mutated AML
NCT00386555	PHASE2	WITHDRAWN	A Phase 2 Study in Patients With Advanced Non-Small Cell Lung Cancer Using New Agents With and Without Docetaxel.
NCT01229644	PHASE2	TERMINATED	Study of Crenolanib, a Selective and Potent Inhibitor of PDGFR, for the Treatment of Adult Gliomas
NCT02283177	PHASE2	COMPLETED	A Safety and Tolerability Study of Crenolanib in Combination With Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia Patients With FLT3 Mutations
NCT02626338	PHASE1/PHASE2	COMPLETED	Pilot Study of Crenolanib Combined With Standard Salvage Chemotherapy in Subjects With R/R AML
NCT02626364	PHASE2	COMPLETED	Study of Crenolanib in Recurrent/Refractory Glioblastoma With PDGFRA Gene Amplification
NCT03324243	PHASE2	WITHDRAWN	A Study of Crenolanib With Fludarabine and Cytarabine in Pediatric Patients With Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia
NCT00949624	PHASE1	COMPLETED	CP-868,596 And CP-868,596 Plus AG-013736 In Combination With Docetaxel In Advanced Solid Tumors
NCT01393912	PHASE1	COMPLETED	PDGFR Inhibitor Crenolanib in Children/Young Adults With Diffuse Intrinsic Pontine Glioma or Recurrent High-Grade Glioma
NCT02270788	PHASE1	COMPLETED	Crenolanib in Combination With Sorafenib in Patients With Refractory or Relapsed Hematologic Malignancies
NCT03193918	PHASE1	COMPLETED	Study of Crenolanib With Ramucirumab and Paclitaxel for Advanced Esophagogastric Adenocarcinoma

Clinical evidence (CIViC)

Variant × indication × effect (20 predictive associations from 21 curated evidence items):

Variant	Indication	Effect	Therapy	Level	CIViC
FLT3 Y572C	Acute Myeloid Leukemia	Sensitivity/Response	Crenolanib	CIViC D	EID12794 +1
FLT3 D593del	Cancer	Sensitivity/Response	Crenolanib + FLT3 Tyrosine Kinase Inhibitor TTT-3002 + Lestaurtinib + Midostaurin	CIViC D	EID11093
FLT3 D835Y	Cancer	Sensitivity/Response	FLT3 Tyrosine Kinase Inhibitor TTT-3002 + Crenolanib + Lestaurtinib + Midostaurin	CIViC D	EID11085
FLT3 E573del	Acute Myeloid Leukemia	Sensitivity/Response	Lestaurtinib + Midostaurin + Quizartinib + Ponatinib + Sorafenib + Crenolanib	CIViC D	EID9307
FLT3 ITD	Cancer	Sensitivity/Response	FLT3 Tyrosine Kinase Inhibitor TTT-3002 + R406 + Ponatinib + Crenolanib + KW2449 + Sorafenib + Sunitinib + Quizartinib + Linifanib + AGS324 + AG1295 + Lestaurtinib + Midostaurin	CIViC D	EID11084
FLT3 Overexpression AND FLT3LG Expression	Cancer	Sensitivity/Response	AG1295 + Crenolanib + R406	CIViC D	EID11089
FLT3 S574del	Acute Myeloid Leukemia	Sensitivity/Response	Lestaurtinib + Crenolanib + Sorafenib + Ponatinib + Quizartinib + Midostaurin	CIViC D	EID9308
FLT3 Y572del	Acute Myeloid Leukemia	Sensitivity/Response	Crenolanib	CIViC D	EID12863
FLT3 Y572del	Acute Myeloid Leukemia	Sensitivity/Response	Midostaurin + Quizartinib + Lestaurtinib + Sorafenib + Crenolanib + Ponatinib	CIViC D	EID9306
PDGFRA D842I	Gastrointestinal Stromal Tumor	Sensitivity/Response	Crenolanib	CIViC D	EID43
PDGFRA D842V	Gastrointestinal Stromal Tumor	Sensitivity/Response	Crenolanib	CIViC D	EID44
PDGFRA D842Y	Gastrointestinal Stromal Tumor	Sensitivity/Response	Crenolanib	CIViC D	EID45
PDGFRA D842_I843delinsVM	Gastrointestinal Stromal Tumor	Sensitivity/Response	Crenolanib	CIViC D	EID47
PDGFRA G853D	Melanoma	Sensitivity/Response	Crenolanib + Imatinib	CIViC D	EID1977
PDGFRA H845Y	Melanoma	Sensitivity/Response	Crenolanib + Imatinib	CIViC D	EID1976
PDGFRA I843DEL	Gastrointestinal Stromal Tumor	Sensitivity/Response	Crenolanib	CIViC D	EID46
PDGFRA P577S	Melanoma	Sensitivity/Response	Imatinib + Crenolanib	CIViC D	EID1974
PDGFRA R841K	Melanoma	Sensitivity/Response	Imatinib + Crenolanib	CIViC D	EID1975
PDGFRA V658A	Melanoma	Sensitivity/Response	Crenolanib	CIViC D	EID8890
FLT3 F691L	Acute Myeloid Leukemia	Resistance	Crenolanib	CIViC D	EID12387

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.

166 molecules share ≥1 primary target. Top 60 by shared-target count:

Molecule	Source	Status	Shared targets
Afatinib	ChEMBL + PubChem	Phase 4 (approved)	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
Crizotinib	ChEMBL + PubChem	Phase 4 (approved)	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
IMATINIB	ChEMBL + PubChem	Phase 4 (approved)	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
PAZOPANIB	ChEMBL + PubChem	Phase 4 (approved)	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
REGORAFENIB	ChEMBL + PubChem	Phase 4 (approved)	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
AXITINIB	ChEMBL	Phase 4 (approved)	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
BOSUTINIB	ChEMBL	Phase 4 (approved)	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
DASATINIB	ChEMBL	Phase 4 (approved)	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
FEDRATINIB	ChEMBL	Phase 4 (approved)	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
MIDOSTAURIN	ChEMBL	Phase 4 (approved)	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
NILOTINIB	ChEMBL	Phase 4 (approved)	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
NINTEDANIB	ChEMBL	Phase 4 (approved)	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
PEXIDARTINIB	ChEMBL	Phase 4 (approved)	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
PONATINIB	ChEMBL	Phase 4 (approved)	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
QUIZARTINIB	ChEMBL	Phase 4 (approved)	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
SORAFENIB	ChEMBL	Phase 4 (approved)	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
SUNITINIB	ChEMBL	Phase 4 (approved)	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
VANDETANIB	ChEMBL	Phase 4 (approved)	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
CEDIRANIB	ChEMBL	Phase 3	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
DOVITINIB	ChEMBL	Phase 3	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
LESTAURTINIB	ChEMBL	Phase 3	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
LINIFANIB	ChEMBL	Phase 3	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
MOTESANIB	ChEMBL	Phase 3	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
SEMAXANIB	ChEMBL	Phase 3	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
VIMSELTINIB	ChEMBL	Phase 3	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
CENISERTIB	ChEMBL	Phase 2	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
DEFOSBARASERTIB	ChEMBL	Phase 2	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
DORAMAPIMOD	ChEMBL	Phase 2	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
FORETINIB	ChEMBL	Phase 2	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
ILORASERTIB	ChEMBL	Phase 2	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
R-406	ChEMBL	Phase 2	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
RAF-265	ChEMBL	Phase 2	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
SOTULETINIB	ChEMBL	Phase 2	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
SU-014813	ChEMBL	Phase 2	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
TANDUTINIB	ChEMBL	Phase 2	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
TOZASERTIB	ChEMBL	Phase 2	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
Idelalisib	PubChem	Approved	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
Selumetinib	PubChem	Approved	CSF1R, FLT3, KIT, PDGFRA, PDGFRB
Gefitinib	ChEMBL + PubChem	Phase 4 (approved)	CSF1R, FLT3, KIT, PDGFRA
ERLOTINIB	ChEMBL	Phase 4 (approved)	FLT3, KIT, PDGFRA, PDGFRB
TIVOZANIB	ChEMBL	Phase 4 (approved)	FLT3, KIT, PDGFRA, PDGFRB
ALVOCIDIB	ChEMBL	Phase 3	CSF1R, FLT3, KIT, PDGFRA
BARASERTIB	ChEMBL	Phase 3	FLT3, KIT, PDGFRA, PDGFRB
BRIVANIB	ChEMBL	Phase 3	CSF1R, KIT, PDGFRA, PDGFRB
CANERTINIB	ChEMBL	Phase 3	FLT3, KIT, PDGFRA, PDGFRB
MASITINIB	ChEMBL	Phase 3	CSF1R, KIT, PDGFRA, PDGFRB
SARACATINIB	ChEMBL	Phase 3	FLT3, KIT, PDGFRA, PDGFRB
VATALANIB	ChEMBL	Phase 3	CSF1R, KIT, PDGFRA, PDGFRB
CEP-32496	ChEMBL	Phase 2	CSF1R, FLT3, KIT, PDGFRB
ENMD-2076	ChEMBL	Phase 2	CSF1R, FLT3, KIT, PDGFRA
REBASTINIB	ChEMBL	Phase 2	CSF1R, FLT3, KIT, PDGFRA
BRIGATINIB	ChEMBL	Phase 4 (approved)	CSF1R, FLT3, KIT
CERITINIB	ChEMBL	Phase 4 (approved)	FLT3, KIT, PDGFRA
ENTRECTINIB	ChEMBL	Phase 4 (approved)	CSF1R, FLT3, KIT
INFIGRATINIB	ChEMBL	Phase 4 (approved)	FLT3, KIT, PDGFRA
LENVATINIB	ChEMBL	Phase 4 (approved)	KIT, PDGFRA, PDGFRB
PACRITINIB	ChEMBL	Phase 4 (approved)	CSF1R, FLT3, PDGFRB
ENZASTAURIN	ChEMBL	Phase 3	FLT3, KIT, PDGFRB
PIMICOTINIB	ChEMBL	Phase 3	CSF1R, KIT, PDGFRA
RUBOXISTAURIN	ChEMBL	Phase 3	FLT3, KIT, PDGFRB