Nemtabrutinib

Summary

Nemtabrutinib (CHEMBL4756476) is a phase-3 clinical-stage small molecule targeting BLK, BMX, and BTK; indicated across 4 conditions including b-cell chronic lymphocytic leukemia and lymphoid neoplasm.

At a glance

• Status: Max clinical phase 3 (not approved)
• Modality: Small molecule
• Targets: 5 (BLK, BMX, BTK…)
• Indications: 4 conditions
• Clinical trials: 21
• Chemistry: 478.9 Da · C25H23ClN4O4

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL4756476
Name	Nemtabrutinib
Type	Small molecule
Max phase	3
FDA approved	no
PubChem CID	129045720
Molecular formula	C25H23ClN4O4
Molecular weight	478.9
InChIKey	JSFCZQSJQXFJDS-QAPCUYQASA-N

SMILES: C1C[C@H](OC[C@@H]1NC2=NC=NC3=C2C(=CN3)C(=O)C4=C(C=C(C=C4)OC5=CC=CC=C5)Cl)CO

IUPAC name: (2-chloro-4-phenoxyphenyl)-[4-[[(3R,6S)-6-(hydroxymethyl)oxan-3-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone

Also known as: ARQ-531, MK-1026, Nemtabrutinib, NEMTABRUTINIB, US11020398, Compound I-123

Patent coverage: 268 distinct patent families (818 SureChEMBL compound mentions), from 3 matched compound structure(s). One matched structure accounts for 677 (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
BLK	BLK proto-oncogene, Src family tyrosine kinase	Inhibition	8.01	0.1%	P51451
BMX	BMX non-receptor tyrosine kinase	Inhibition	8.28	0%	P51813
BTK	Bruton tyrosine kinase	Inhibition	8.6	0.7%	Q06187
TEC	tec protein tyrosine kinase	Inhibition	8.24	0.1%	P42680
YES1	YES proto-oncogene 1, Src family tyrosine kinase	Inhibition	8.38	0.7%	P07947

Broader ChEMBL bioactivity targets: 1 (assay-derived). Sample: Tyrosine-protein kinase BTK.

Bioactivity

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

Target	pChembl	Type	Value	Unit	Activity ID
BTK	9.41	IC50	0.39	nM	CHEMBL_ACT_22395822
BTK	9.41	IC50	0.39	nM	CHEMBL_ACT_24773313
BTK	9.41	IC50	0.39	nM	CHEMBL_ACT_25464224
BTK	9.41	IC50	0.39	nM	CHEMBL_ACT_28359776
BTK	9.07	IC50	0.85	nM	CHEMBL_ACT_22395823
BTK	9.07	IC50	0.85	nM	CHEMBL_ACT_24773312
BTK	9.07	IC50	0.85	nM	CHEMBL_ACT_25030297
BTK	9.07	IC50	0.85	nM	CHEMBL_ACT_25464223
BTK	9.07	IC50	0.85	nM	CHEMBL_ACT_28359449
BTK	9.07	IC50	0.85	nM	CHEMBL_ACT_28359773

Target pathways

Aggregated over 5 target gene(s): BLK, BMX, BTK, TEC, YES1.

Top Reactome pathways

79 total, by targets touching each:

Pathway	Targets	Genes
Immune System	3	BLK, BTK, TEC
Adaptive Immune System	2	BLK, BTK
Signaling by SCF-KIT	2	TEC, YES1
Signal Transduction	2	BTK, TEC
Innate Immune System	2	BTK, TEC
Fc epsilon receptor (FCERI) signaling	2	BTK, TEC
FCERI mediated Ca+2 mobilization	2	BTK, TEC
FCGR3A-mediated phagocytosis	2	BTK, YES1
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	2	BLK, BTK
Signaling by the B Cell Receptor (BCR)	2	BLK, BTK
Apoptosis	1	BMX
Apoptotic cleavage of cellular proteins	1	BMX
Signaling by ERBB2	1	YES1
ER-Phagosome pathway	1	BTK
Antigen processing-Cross presentation	1	BTK
Cytokine Signaling in Immune system	1	TEC
Metabolism	1	BMX
Regulation of KIT signaling	1	YES1
PI Metabolism	1	BMX
Phospholipid metabolism	1	BMX
Disease	1	BTK
Toll Like Receptor 4 (TLR4) Cascade	1	BTK
Synthesis of PIPs at the plasma membrane	1	BMX
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	1	BTK
Toll Like Receptor TLR1:TLR2 Cascade	1	BTK
Toll Like Receptor TLR6:TLR2 Cascade	1	BTK
Toll-like Receptor Cascades	1	BTK
Toll Like Receptor 2 (TLR2) Cascade	1	BTK
Signaling by Rho GTPases	1	BTK
RHO GTPase Effectors	1	BTK

Dominant GO biological processes

GO term	Targets
protein phosphorylation	5
intracellular signal transduction	4
B cell receptor signaling pathway	4
adaptive immune response	3
cell surface receptor protein tyrosine kinase signaling pathway	2
peptidyl-tyrosine phosphorylation	2
cell differentiation	2
apoptotic process	2
mesoderm development	2
T cell receptor signaling pathway	2
immune system process	2
positive regulation of insulin secretion	1
immune response-activating cell surface receptor signaling pathway	1
phosphatidylinositol biosynthetic process	1
cell adhesion	1

Indications & clinical

Indications

4 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
B-cell chronic lymphocytic leukemia	3	MONDO:0004948	EFO:0000095
lymphoid neoplasm	1	MONDO:0005157	EFO:0001642
neoplasm	1	MONDO:0005070	EFO:0000616
liver disorder	1	MONDO:0005154	EFO:0001421

Clinical trials

Total trials: 21.

Phase distribution

Phase	Trials
PHASE1	10
PHASE2	7
PHASE3	3
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05624554	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Nemtabrutinib vs Chemoimmunotherapy for Participants With Previously Untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Without TP53 Aberrations (MK-1026-008, BELLWAVE-008)
NCT05947851	PHASE3	RECRUITING	A Study of Nemtabrutinib Plus Venetoclax vs Venetoclax + Rituximab (VR) in Second-line (2L) + Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) (MK-1026-010/BELLWAVE-010).
NCT06136559	PHASE3	RECRUITING	A Study of Nemtabrutinib (MK-1026) Versus Comparator (Investigator’s Choice of Ibrutinib or Acalabrutinib) in First Line (1L) Chronic Lymphocytic Leukemia (CLL)/ Small Lymphocytic Lymphoma (SLL) (MK-1026-011/BELLWAVE-011)
NCT03162536	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study of Nemtabrutinib (MK-1026) in Participants With Relapsed or Refractory Hematologic Malignancies (ARQ 531-101/MK-1026-001)
NCT04728893	PHASE2	RECRUITING	Efficacy and Safety of Nemtabrutinib (MK-1026) in Participants With Hematologic Malignancies (MK-1026-003)
NCT05458297	PHASE2	ACTIVE_NOT_RECRUITING	A Study of Zilovertamab Vedotin (MK-2140) as Monotherapy and in Combination in Participants With Aggressive and Indolent B-cell Malignancies (MK-2140-006)
NCT06572618	PHASE2	RECRUITING	Nemtabrutinib With Rituximab for the Treatment of Patients With Mantle Cell Lymphoma
NCT06863402	PHASE2	RECRUITING	Nemtabrutinib and Pembrolizumab for the Treatment of Richter Transformation, Diffuse Large B-cell Lymphoma Subtype
NCT07194980	PHASE2	RECRUITING	Nemtabrutinib and Lisocabtagene Maraleucel for the Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
NCT07557056	PHASE2	NOT_YET_RECRUITING	Nemtabrutinib and Venetoclax for the Treatment of Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
NCT07583810	PHASE2	NOT_YET_RECRUITING	Non-covalent BTK Inhibitor Nemtabrutinib in Combination With the CD20 Monoclonal Antibody Rituximab for the Treatment of Marginal Zone Lymphoma
NCT05347225	PHASE1	ACTIVE_NOT_RECRUITING	A Study of Nemtabrutinib (MK-1026) in China Participants With Relapsed or Refractory Hematologic Malignancies (MK-1026-005)
NCT06442436	PHASE1	RECRUITING	A Study of Nemtabrutinib in Participants With Moderate Hepatic Impairment (MK-1026-015)
NCT05673460	PHASE1	COMPLETED	A Clinical Study of Nemtabrutinib in Japanese Participants With Hematological Malignancies (MK-1026-002)
NCT06586671	PHASE1	COMPLETED	A Study to Compare Forms of Nemtabrutinib (MK-1026) in Healthy Adult Participants (MK-1026-007)
NCT06625827	PHASE1	COMPLETED	A Study of the Effect of Nemtabrutinib (MK-1026) on the Plasma Levels of Digoxin in Healthy Participants (MK-1026-012)
NCT06688045	PHASE1	COMPLETED	A Study of the Effects of Itraconazole on the Plasma Levels of Nemtabrutinib (MK-1026-013)
NCT06698016	PHASE1	COMPLETED	A Study of the Effect of Efavirenz on the Plasma Levels of Nemtabrutinib (MK-1026-014)
NCT06772805	PHASE1	COMPLETED	A Study to Evaluate the Effect of Food on Nemtabrutinib (MK-1026) in Healthy Participants (MK-1026-016)
NCT06772818	PHASE1	COMPLETED	A Study to Evaluate the Effect of Food on Nemtabrutinib (MK-1026) in Healthy Participants (MK-1026-017)
NCT07232589	PHASE1	COMPLETED	A Study of the Effect of Diltiazem on the Plasma Levels of Nemtabrutinib (MK-1026-022)

Clinical evidence (CIViC)

No CIViC predictive evidence (expected for non-precision-medicine drugs).

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.

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

Molecule	Source	Status	Shared targets
AFATINIB	ChEMBL + PubChem	Phase 4 (approved)	BLK, BMX, BTK, TEC, YES1
BOSUTINIB	ChEMBL + PubChem	Phase 4 (approved)	BLK, BMX, BTK, TEC, YES1
CRIZOTINIB	ChEMBL + PubChem	Phase 4 (approved)	BLK, BMX, BTK, TEC, YES1
FEDRATINIB	ChEMBL + PubChem	Phase 4 (approved)	BLK, BMX, BTK, TEC, YES1
IBRUTINIB	ChEMBL + PubChem	Phase 4 (approved)	BLK, BMX, BTK, TEC, YES1
PAZOPANIB	ChEMBL + PubChem	Phase 4 (approved)	BLK, BMX, BTK, TEC, YES1
SUNITINIB	ChEMBL + PubChem	Phase 4 (approved)	BLK, BMX, BTK, TEC, YES1
VANDETANIB	ChEMBL + PubChem	Phase 4 (approved)	BLK, BMX, BTK, TEC, YES1
ZANUBRUTINIB	ChEMBL + PubChem	Phase 4 (approved)	BLK, BMX, BTK, TEC, YES1
DASATINIB	ChEMBL	Phase 4 (approved)	BLK, BMX, BTK, TEC, YES1
CANERTINIB	ChEMBL	Phase 3	BLK, BMX, BTK, TEC, YES1
LESTAURTINIB	ChEMBL	Phase 3	BLK, BMX, BTK, TEC, YES1
FORETINIB	ChEMBL	Phase 2	BLK, BMX, BTK, TEC, YES1
R-406	ChEMBL	Phase 2	BLK, BMX, BTK, TEC, YES1
TOZASERTIB	ChEMBL	Phase 2	BLK, BMX, BTK, TEC, YES1
Idelalisib	PubChem	Approved	BLK, BMX, BTK, TEC, YES1
Selumetinib	PubChem	Approved	BLK, BMX, BTK, TEC, YES1
AXITINIB	ChEMBL + PubChem	Phase 4 (approved)	BLK, BMX, TEC, YES1
BRIGATINIB	ChEMBL + PubChem	Phase 4 (approved)	BLK, BTK, TEC, YES1
ERLOTINIB	ChEMBL + PubChem	Phase 4 (approved)	BLK, BMX, TEC, YES1
GEFITINIB	ChEMBL + PubChem	Phase 4 (approved)	BLK, BMX, TEC, YES1
NILOTINIB	ChEMBL + PubChem	Phase 4 (approved)	BLK, BMX, TEC, YES1
QUIZARTINIB	ChEMBL + PubChem	Phase 4 (approved)	BLK, BMX, TEC, YES1
RITLECITINIB	ChEMBL + PubChem	Phase 4 (approved)	BLK, BMX, BTK, TEC
ACALABRUTINIB	ChEMBL	Phase 4 (approved)	BLK, BMX, BTK, TEC
TIRABRUTINIB	ChEMBL	Phase 4 (approved)	BLK, BMX, BTK, TEC
REMIBRUTINIB	ChEMBL	Phase 3	BLK, BMX, BTK, TEC
RILZABRUTINIB	ChEMBL	Phase 3	BLK, BMX, BTK, TEC
ATUZABRUTINIB	ChEMBL	Phase 2	BLK, BMX, BTK, TEC
BMS-986142	ChEMBL	Phase 2	BLK, BMX, BTK, TEC
PELITINIB	ChEMBL	Phase 2	BLK, BMX, BTK, YES1
REBASTINIB	ChEMBL	Phase 2	BLK, BMX, BTK, YES1
Mobocertinib	PubChem	Approved	BLK, BMX, BTK, TEC
ENTRECTINIB	ChEMBL + PubChem	Phase 4 (approved)	BLK, BTK, TEC
IMATINIB	ChEMBL + PubChem	Phase 4 (approved)	BLK, BMX, TEC
PONATINIB	ChEMBL + PubChem	Phase 4 (approved)	BTK, TEC, YES1
SORAFENIB	ChEMBL + PubChem	Phase 4 (approved)	BLK, BMX, TEC
NERATINIB	ChEMBL	Phase 4 (approved)	BLK, BTK, YES1
NINTEDANIB	ChEMBL	Phase 4 (approved)	BLK, BTK, YES1
CEDIRANIB	ChEMBL	Phase 3	BLK, BTK, YES1
DOVITINIB	ChEMBL	Phase 3	BLK, BTK, YES1
EVOBRUTINIB	ChEMBL	Phase 3	BMX, BTK, TEC
AT-9283	ChEMBL	Phase 2	BTK, TEC, YES1
BIIB-091	ChEMBL	Phase 2	BMX, BTK, TEC
BMS-919373	ChEMBL	Phase 2	BMX, BTK, TEC
BRANEBRUTINIB	ChEMBL	Phase 2	BMX, BTK, TEC
DANUSERTIB	ChEMBL	Phase 2	BTK, TEC, YES1
DEFOSBARASERTIB	ChEMBL	Phase 2	BLK, BTK, YES1
MILREBRUTINIB	ChEMBL	Phase 2	BMX, BTK, TEC
SPEBRUTINIB	ChEMBL	Phase 2	BMX, BTK, TEC
SU-014813	ChEMBL	Phase 2	BLK, BTK, YES1
Binimetinib	PubChem	Approved	BTK, TEC, YES1
dacomitinib	PubChem	Approved	BTK, TEC, YES1
Fostamatinib	PubChem	Approved	BTK, TEC, YES1
Lapatinib	PubChem	Approved	BLK, BMX, TEC
regorafenib	PubChem	Approved	BTK, TEC, YES1
Trametinib	PubChem	Approved	BTK, TEC, YES1
BELUMOSUDIL	ChEMBL + PubChem	Phase 4 (approved)	BLK, BTK
CERITINIB	ChEMBL + PubChem	Phase 4 (approved)	BTK, TEC
Dabrafenib	ChEMBL + PubChem	Phase 4 (approved)	TEC, YES1