Navitoclax

Summary

Navitoclax (CHEMBL443684) is a phase-3 clinical-stage small-molecule B-cell lymphoma 2 inhibitor (ATC L01XX78) targeting BCL2 and BCL2L1; indicated across 16 conditions including neoplasm and primary myelofibrosis.

At a glance

• Status: Max clinical phase 3 (not approved)
• Modality: Small molecule
• ATC class: L01XX78
• Targets: 2 (BCL2, BCL2L1)
• Indications: 16 conditions
• Clinical trials: 44
• Chemistry: 974.6 Da · C47H55ClF3N5O6S3

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL443684
Name	Navitoclax
Type	Small molecule
Max phase	3
FDA approved	no
PubChem CID	24978538
ChEBI	CHEBI:131174
ATC	L01XX78
Molecular formula	C47H55ClF3N5O6S3
Molecular weight	974.6
InChIKey	JLYAXFNOILIKPP-KXQOOQHDSA-N

SMILES: CC1(CCC(=C(C1)CN2CCN(CC2)C3=CC=C(C=C3)C(=O)NS(=O)(=O)C4=CC(=C(C=C4)N[C@H](CCN5CCOCC5)CSC6=CC=CC=C6)S(=O)(=O)C(F)(F)F)C7=CC=C(C=C7)Cl)C

IUPAC name: 4-[4-[[2-(4-chlorophenyl)-5,5-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-morpholin-4-yl-1-phenylsulfanylbutan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide

ChEBI definition: A N-sulfonylcarboxamide resulting from the formal condensation of the carboxy group of 4-{4-[(4’-chloro-4,4-dimethyl-3,4,5,6-tetrahydro[biphenyl]-2-yl)methyl]piperazin-1-yl}benzoic acid with the amino group of 4-{[(2R)-4-(morpholin-4-yl)-1-(phenylsulfanyl)butan-2-yl]amino}-3-[(trifluoromethyl)sulfonyl]benzenesulfonamide. It is a BH3-mimetic drug which targets the anti-apoptotic B-cell lymphoma-2 (BCL-2) family proteins, including BCL-2, BCL-xL, and BCL-w, and induces apoptosis in cancer cells. Currently under clinical investigation as treatment for solid tumors and hematologic malignancies.

Pharmacological roles (ChEBI): B-cell lymphoma 2 inhibitor, apoptosis inducer, antineoplastic agent.

Also known as: A-855071.0, ABT-263, Navitoclax, SID124899202, navitoclax, NAVITOCLAX, SID99460835, NavitoclaxÊ, NavitoclaxÂ

Parent form; salt/anhydrous children: CHEMBL2105690

Patent coverage: 1,822 distinct patent families (4,791 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 4,558 (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
BCL2	BCL2 apoptosis regulator	Antagonist	9	3.3%	P10415
BCL2L1	Bcl-2-like 1	Antagonist	9	86.5%	Q07817

Broader ChEMBL bioactivity targets: 8 (assay-derived). Sample: Cytochrome P450 2C9, Bcl2-associated agonist of cell death, Bcl-xL/Bcl-2-like protein 11, Induced myeloid leukemia cell differentiation protein Mcl-1, Bcl-2-like protein 1, Bcl-2-like protein 2, Aspartyl/asparaginyl beta-hydroxylase, Apoptosis regulator Bcl-2.

Bioactivity

ChEMBL activities: 34 potent at pChembl ≥ 5 of 34 total. Top 100 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
BCL2	10.36	Ki	0.04	nM	CHEMBL_ACT_18568190
BCL2	10.36	Ki	0.04	nM	CHEMBL_ACT_18916447
BCL2	10.36	Ki	0.04	nM	CHEMBL_ACT_26314232
BCL2L1	10.26	Ki	0.06	nM	CHEMBL_ACT_18568194
BCL2L1	10.26	Ki	0.06	nM	CHEMBL_ACT_26314238
BCL2	9.19	Kd	0.65	nM	CHEMBL_ACT_24505539
BCL2	8.7	IC50	2	nM	CHEMBL_ACT_19282972
BCL2L1	8.68	Kd	2.07	nM	CHEMBL_ACT_24505535
BCL2L1	8.48	IC50	3.3	nM	CHEMBL_ACT_13951159
BCL2L11	8.37	IC50	4.3	nM	CHEMBL_ACT_15142797
BCL2L1	8.09	IC50	8.2	nM	CHEMBL_ACT_18472128
BCL2	7.99	IC50	10.3	nM	CHEMBL_ACT_18472120
BCL2	7.99	IC50	10.3	nM	CHEMBL_ACT_26187997
BCL2	7.69	Kd	20.6	nM	CHEMBL_ACT_22775788
BCL2L2-PABPN1	7.68	Ki	21	nM	CHEMBL_ACT_26314250
BCL2L1	7.44	Ki	36	nM	CHEMBL_ACT_3526124
BCL2L1	7.32	Ki	48	nM	CHEMBL_ACT_18997200
BCL2	7.26	Kd	55	nM	CHEMBL_ACT_28689203
BCL2L1	7.26	Kd	55	nM	CHEMBL_ACT_28689206
BCL2	7.26	Kd	55	nM	CHEMBL_ACT_28703504
BAD	7.26	Kd	55	nM	CHEMBL_ACT_28703507
BCL2	7.26	Kd	55	nM	CHEMBL_ACT_28956056
BCL2L1	7.26	Kd	55	nM	CHEMBL_ACT_28956059
BCL2L1	7.22	IC50	60	nM	CHEMBL_ACT_15040236
BCL2L2-PABPN1	7.16	IC50	70	nM	CHEMBL_ACT_19282984
BCL2L2-PABPN1	6.61	Ki	245	nM	CHEMBL_ACT_18997202
MCL1	6.3	IC50	500	nM	CHEMBL_ACT_16623345
MCL1	6.26	Ki	550	nM	CHEMBL_ACT_18390902
ASPH	6.1	IC50	800	nM	CHEMBL_ACT_22416354
ASPH	5.99	IC50	1030	nM	CHEMBL_ACT_22416330
ASPH	5.92	IC50	1210	nM	CHEMBL_ACT_22416366
ASPH	5.88	IC50	1330	nM	CHEMBL_ACT_22416342
CYP2C9	5.82	IC50	1500	nM	CHEMBL_ACT_28777661
BCL2	5.74	Kd	1803	nM	CHEMBL_ACT_22775790

Target pathways

Aggregated over 2 target gene(s): BCL2, BCL2L1.

Top Reactome pathways

45 total, by targets touching each:

Pathway	Targets	Genes
Apoptosis	2	BCL2, BCL2L1
Intrinsic Pathway for Apoptosis	2	BCL2, BCL2L1
BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members	2	BCL2, BCL2L1
Cytokine Signaling in Immune system	2	BCL2, BCL2L1
Signal Transduction	2	BCL2, BCL2L1
Innate Immune System	2	BCL2, BCL2L1
Immune System	2	BCL2, BCL2L1
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	2	BCL2, BCL2L1
Cellular responses to stress	2	BCL2, BCL2L1
Signaling by Interleukins	2	BCL2, BCL2L1
Programmed Cell Death	2	BCL2, BCL2L1
Inflammasomes	2	BCL2, BCL2L1
Interleukin-4 and Interleukin-13 signaling	2	BCL2, BCL2L1
The NLRP1 inflammasome	2	BCL2, BCL2L1
Cellular responses to stimuli	2	BCL2, BCL2L1
Cellular response to chemical stress	2	BCL2, BCL2L1
KEAP1-NFE2L2 pathway	2	BCL2, BCL2L1
Nuclear events mediated by NFE2L2	2	BCL2, BCL2L1
NFE2L2 regulating tumorigenic genes	2	BCL2, BCL2L1
Activation of BAD and translocation to mitochondria	1	BCL2
Activation of BH3-only proteins	1	BCL2
Developmental Biology	1	BCL2
Disease	1	BCL2L1
Diseases of signal transduction by growth factor receptors and second messengers	1	BCL2L1
Infectious disease	1	BCL2L1
RAF/MAP kinase cascade	1	BCL2L1
MAPK family signaling cascades	1	BCL2L1
MAPK1/MAPK3 signaling	1	BCL2L1
ESR-mediated signaling	1	BCL2
Signaling by Nuclear Receptors	1	BCL2
Extra-nuclear estrogen signaling	1	BCL2
Estrogen-dependent gene expression	1	BCL2
Estrogen-dependent nuclear events downstream of ESR-membrane signaling	1	BCL2
RAS processing	1	BCL2L1
SARS-CoV-1 Infection	1	BCL2L1
SARS-CoV Infections	1	BCL2L1
FLT3 signaling in disease	1	BCL2L1
SARS-CoV-1-mediated effects on programmed cell death	1	BCL2L1
SARS-CoV-1-host interactions	1	BCL2L1
STAT5 activation downstream of FLT3 ITD mutants	1	BCL2L1
Signaling by FLT3 ITD and TKD mutants	1	BCL2L1
MITF-M-regulated melanocyte development	1	BCL2
Viral Infection Pathways	1	BCL2L1
Regulation of MITF-M-dependent genes involved in apoptosis	1	BCL2
MITF-M-dependent gene expression	1	BCL2

Dominant GO biological processes

GO term	Targets
ovarian follicle development	2
release of cytochrome c from mitochondria	2
apoptotic process	2
male gonad development	2
intrinsic apoptotic signaling pathway in response to DNA damage	2
response to radiation	2
negative regulation of autophagy	2
response to cytokine	2
positive regulation of apoptotic process	2
negative regulation of apoptotic process	2
negative regulation of neuron apoptotic process	2
regulation of mitochondrial membrane permeability	2
neuron apoptotic process	2
defense response to virus	2
regulation of mitochondrial membrane potential	2

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
neoplasm	3	MONDO:0005070	EFO:0000616
primary myelofibrosis	3	MONDO:0009692	EFO:0002430
B-cell chronic lymphocytic leukemia	2	MONDO:0004948	EFO:0000095
diffuse large B-cell lymphoma	2	MONDO:0018905	EFO:0000403
ovarian cancer	2	MONDO:0008170	MONDO:0008170
mantle cell lymphoma	2	MONDO:0018876	EFO:1001469
small cell lung carcinoma	1	MONDO:0008433	EFO:0000702
lymphoid neoplasm	1	MONDO:0005157	EFO:0001642
acute lymphoblastic leukemia	1	MONDO:0004967	EFO:0000220
acute myeloid leukemia	1	MONDO:0018874	EFO:0000222
myelodysplastic syndrome	1	MONDO:0018881	EFO:0000198
leukemia	1	MONDO:0005059	EFO:0000565
lymphoid leukemia	1	MONDO:0005402	EFO:0004289

3 further indication records had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.

Clinical trials

Total trials: 44.

Phase distribution

Phase	Trials
PHASE1	22
PHASE1/PHASE2	9
PHASE2	9
PHASE3	2
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04468984	PHASE3	ACTIVE_NOT_RECRUITING	Study of Oral Navitoclax Tablet in Combination With Oral Ruxolitinib Tablet Versus Best Available Therapy to Assess Change in Spleen Volume in Adult Participants With Relapsed/Refractory Myelofibrosis
NCT04472598	PHASE3	COMPLETED	Study of Oral Navitoclax Tablet In Combination With Oral Ruxolitinib Tablet When Compared With Oral Ruxolitinib Tablet To Assess Change In Spleen Volume In Adult Participants With Myelofibrosis
NCT01989585	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Testing the Addition of Navitoclax to the Combination of Dabrafenib and Trametinib in People Who Have BRAF Mutant Melanoma
NCT02079740	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Trametinib and Navitoclax in Treating Patients With Advanced or Metastatic Solid Tumors
NCT05054465	PHASE1/PHASE2	NOT_YET_RECRUITING	A Phase 1b-2 Trial to Assess Venetoclax and Navitoclax Consolidation and Post-transplant Maintenance in High-risk Patients With T-ALL
NCT05192889	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Trial Treating Relapsed Acute Lymphoblastic Leukemia With Venetoclax and Navitoclax
NCT05864742	PHASE2	ACTIVE_NOT_RECRUITING	Genetically Risk-Stratified Venetoclax, Ibrutinib, Rituximab (± Navitoclax) in Relapsed/Refractory Mantle Cell Lymphoma
NCT00406809	PHASE1/PHASE2	COMPLETED	A Study of ABT-263 in Subjects With Relapsed or Refractory Lymphoid Malignancies
NCT00445198	PHASE1/PHASE2	COMPLETED	A Phase 1/2a Study of ABT-263 in Subjects With Small Cell Lung Cancer (SCLC) or Other Non-Hematological Malignancies
NCT00481091	PHASE1/PHASE2	COMPLETED	A Study of ABT-263 in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia
NCT00918450	PHASE2	WITHDRAWN	Study Assessing the Safety and Efficacy of ABT-263 in Subjects With B-cell Chronic Lymphocytic Leukemia (CLL) Who Have Failed at Least One Prior Fludarabine-containing Regimen
NCT01087151	PHASE2	COMPLETED	A Study of ABT-263 in Combination With Dose-Intensive Rituximab, or Dose-Intensive Rituximab Alone, in Previously Untreated Patients With B-Cell, Chronic Lymphocytic Leukemia (CLL)
NCT01423539	PHASE2	WITHDRAWN	A Study of Navitoclax in Addition to Bendamustine and Rituximab in Patients With Relapsed Diffuse Large B-Cell Lymphoma (NAVIGATE)
NCT01557777	PHASE2	COMPLETED	Open-label Extension Study of Navitoclax in Subjects With Chronic Lymphocytic Leukemia (CLL)
NCT01828476	PHASE2	TERMINATED	Navitoclax and Abiraterone Acetate With or Without Hydroxychloroquine in Treating Patients With Progressive Metastatic Castrate Refractory Prostate Cancer
NCT02591095	PHASE2	COMPLETED	A Study of ABT-263 as Single Agent in Women With Platinum Resistant/Refractory Recurrent Ovarian Cancer
NCT03222609	PHASE2	COMPLETED	A Study Evaluating Tolerability and Efficacy of Navitoclax Alone or in Combination With Ruxolitinib in Participants With Myelofibrosis
NCT03366103	PHASE1/PHASE2	TERMINATED	Navitoclax and Vistusertib in Treating Patients With Relapsed Small Cell Lung Cancer and Other Solid Tumors
NCT05740449	PHASE1/PHASE2	WITHDRAWN	HEM-iSMART-A: Decitabine / Venetoclax and Navitoclax in Pediatric Patients With Relapsed or Refractory Hematological Malignancies
NCT06210750	PHASE2	WITHDRAWN	Adding Targeted Drugs to Usual Chemotherapy for Adults With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia (T-ALL) and T-Cell Lymphoblastic Lymphoma (T-LBL)
NCT04041050	PHASE1	ACTIVE_NOT_RECRUITING	A Study Evaluating Safety and Tolerability, and Pharmacokinetics of Navitoclax Monotherapy and in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasm
NCT04454658	PHASE1	ACTIVE_NOT_RECRUITING	Safety and Tolerability Study of Oral ABBV-744 Tablet Alone or in Combination With Oral Ruxolitinib Tablet or Oral Navitoclax Tablet in Adult Participants With Myelofibrosis
NCT05222984	PHASE1	ACTIVE_NOT_RECRUITING	Navitoclax, Venetoclax, and Decitabine for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia Previously Treated With Venetoclax
NCT05358639	PHASE1	ACTIVE_NOT_RECRUITING	Combination of Olaparib and Navitoclax in Women with HGSC and TNBC
NCT05455294	PHASE1	ACTIVE_NOT_RECRUITING	Combination Navitoclax, Venetoclax and Decitabine for Advanced Myeloid Neoplasms
NCT00743028	PHASE1	COMPLETED	Assess the Oral Bioavailability of New ABT-263 Formulations
NCT00788684	PHASE1	COMPLETED	Safety Study of ABT-263 in Combination With Rituximab in Lymphoid Cancers
NCT00868413	PHASE1	COMPLETED	Study of ABT-263 When Administered in Combination With Either Fludarabine/Cyclophosphamide/Rituximab or Bendamustine/Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia
NCT00878449	PHASE1	COMPLETED	A Study Evaluating the Safety of ABT-263 in Combination With Etoposide/Cisplatin in Subjects With Cancer
NCT00887757	PHASE1	COMPLETED	Safety Study of ABT-263 in Combination With Gemzar (Gemcitabine) in Subjects With Solid Tumors
NCT00888108	PHASE1	COMPLETED	Safety Profile, MTD, and PK Profile Studies of ABT-263 When Administered in Combination With Standard and Weekly Regimens of Docetaxel in Subjects With Cancer
NCT00891605	PHASE1	COMPLETED	Safety Study of ABT-263 in Combination With Paclitaxel in Subjects With Solid Tumors
NCT00982566	PHASE1	COMPLETED	Assess the Oral Bioavailability of a New ABT-263 Formulation in Subjects With Cancer
NCT01009073	PHASE1	COMPLETED	A Study Evaluating ABT-263 With Erlotinib, ABT-263 With Irinotecan, and ABT-263 Monotherapy in Cancer Subjects
NCT01021358	PHASE1	COMPLETED	A Study to Assess the Effect of Ketoconazole on the Metabolism of ABT-263 (Navitoclax).
NCT01053520	PHASE1	COMPLETED	Assess the Oral Bioavailability of a New ABT-263 Formulation in Healthy Female Subjects
NCT01121133	PHASE1	COMPLETED	A Study to Assess the Effect of Rifampin on the Metabolism of Navitoclax
NCT02143401	PHASE1	COMPLETED	Navitoclax and Sorafenib Tosylate in Treating Patients With Relapsed or Refractory Solid Tumors
NCT02520778	PHASE1	COMPLETED	Osimertinib and Navitoclax in Treating Patients With EGFR-Positive Previously Treated Advanced or Metastatic Non-small Cell Lung Cancer
NCT03181126	PHASE1	COMPLETED	A Study of Venetoclax in Combination With Navitoclax and Chemotherapy in Subjects With Relapsed/Refractory Acute Lymphoblastic Leukemia or Relapsed/Refractory Lymphoblastic Lymphoma
NCT04480086	PHASE1	TERMINATED	Safety and Tolerability Study of Mivebresib Tablet Alone or in Combination With Ruxolitinib Tablet or Navitoclax Tablet in Adult Participants With Myelofibrosis
NCT05564650	PHASE1	COMPLETED	Navitoclax in Relapsed or Refractory High-Risk Myelodysplastic Syndrome
NCT03592576	Not specified	NO_LONGER_AVAILABLE	Expanded Access to Navitoclax
NCT05215405	Not specified	NO_LONGER_AVAILABLE	Expanded Access Program of Venetoclax and Navitoclax for Pediatric Patients with Relapsed or Refractory ALL or LL

Clinical evidence (CIViC)

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

Pharmacology

Pharmacogenomics

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

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.

11 molecules share ≥1 primary target. Top 11 by shared-target count:

Molecule	Source	Status	Shared targets
VENETOCLAX	ChEMBL	Phase 4 (approved)	BCL2, BCL2L1
EPIGALOCATECHIN GALLATE	ChEMBL	Phase 3	BCL2, BCL2L1
GOSSYPOL	ChEMBL	Phase 3	BCL2, BCL2L1
OBATOCLAX	ChEMBL	Phase 3	BCL2, BCL2L1
SONROTOCLAX	ChEMBL	Phase 3	BCL2, BCL2L1
IXABEPILONE	ChEMBL	Phase 4 (approved)	BCL2
METHYSERGIDE	ChEMBL	Phase 4 (approved)	BCL2L1
ASARETOCLAX	ChEMBL	Phase 2	BCL2L1
CHLORCYCLIZINE	ChEMBL	Phase 2	BCL2
FORMONONETIN	ChEMBL	Phase 2	BCL2
LACUTOCLAX	ChEMBL	Phase 2	BCL2