Afuresertib

Summary

Afuresertib (CHEMBL2219422) is a phase-3 clinical-stage small molecule targeting AKT1, AKT2, and AKT3; indicated across 7 conditions including breast neoplasm and langerhans cell histiocytosis.

At a glance

• Status: Max clinical phase 3 (not approved)
• Modality: Small molecule
• Targets: 3 (AKT1, AKT2, AKT3)
• Indications: 7 conditions
• Clinical trials: 12
• Chemistry: 427.3 Da · C18H17Cl2FN4OS

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL2219422
Name	Afuresertib
Type	Small molecule
Max phase	3
FDA approved	no
PubChem CID	46843057
Molecular formula	C18H17Cl2FN4OS
Molecular weight	427.3
InChIKey	AFJRDFWMXUECEW-LBPRGKRZSA-N

SMILES: CN1C(=C(C=N1)Cl)C2=C(SC(=C2)C(=O)N[C@@H](CC3=CC(=CC=C3)F)CN)Cl

IUPAC name: N-[(2S)-1-amino-3-(3-fluorophenyl)propan-2-yl]-5-chloro-4-(4-chloro-1-methylpyrazol-5-yl)thiophene-2-carboxamide

Also known as: Afuresertib, ASB-183, ASB183, Gsk-2110183, GSK-2110183, GSK-2110183C, GSK2110183, GSK2110183C, AFURESERTIB

Parent form; salt/anhydrous children: CHEMBL2219423

Patent coverage: 569 distinct patent families (1,467 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 1,202 (82%) 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
AKT1	AKT serine/threonine kinase 1	Inhibition	10.1	3.4%	P31749
AKT2	AKT serine/threonine kinase 2	Inhibition	8.7	2.6%	P31751
AKT3	AKT serine/threonine kinase 3	Inhibition	8.59	0.2%	Q9Y243

Broader ChEMBL bioactivity targets: 12 (assay-derived). Sample: RAC-beta serine/threonine-protein kinase, cAMP-dependent protein kinase catalytic subunit beta, Rho-associated protein kinase 2, Protein kinase C alpha type, Protein kinase C beta type, Rho-associated protein kinase 1, Serine/threonine-protein kinase N1, cAMP-dependent protein kinase catalytic subunit alpha, RAC-alpha serine/threonine-protein kinase, RAC-gamma serine/threonine-protein kinase.

Bioactivity

ChEMBL activities: 21 potent at pChembl ≥ 5 of 22 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
AKT1	10.1	Ki	0.08	nM	CHEMBL_ACT_18854052
AKT1	10.1	IC50	0.08	nM	CHEMBL_ACT_24978767
AKT1	10.1	Ki	0.08	nM	CHEMBL_ACT_25990832
AKT1	9	IC50	1	nM	CHEMBL_ACT_16881166
AKT3	8.8	IC50	1.58	nM	CHEMBL_ACT_16881208
AKT2	8.7	IC50	2	nM	CHEMBL_ACT_24978769
AKT2	8.7	Ki	2	nM	CHEMBL_ACT_25990833
AKT3	8.59	IC50	2.6	nM	CHEMBL_ACT_24978771
AKT3	8.15	Kd	7	nM	CHEMBL_ACT_17883278
AKT2	8	IC50	10	nM	CHEMBL_ACT_16881187
AKT1	7.77	IC50	16.9	nM	CHEMBL_ACT_18854048
AKT1	7.2	Kd	63	nM	CHEMBL_ACT_17882787
PRKACA	6.88	Kd	133	nM	CHEMBL_ACT_17928574
PRKACB	6.68	Kd	211	nM	CHEMBL_ACT_17928662
PKN1	6.06	Kd	880	nM	CHEMBL_ACT_17927325
ROCK1	5.67	Kd	2144	nM	CHEMBL_ACT_17935943
AKT2	5.55	Kd	2800	nM	CHEMBL_ACT_17883062
PRKD2	5.41	Kd	3911	nM	CHEMBL_ACT_17931417
CIT	5.37	Kd	4258	nM	CHEMBL_ACT_17892237
ROCK2	5.33	Kd	4733	nM	CHEMBL_ACT_17936160
PRKCB	5.31	Kd	4879	nM	CHEMBL_ACT_17930136

Target pathways

Aggregated over 3 target gene(s): AKT1, AKT2, AKT3.

Top Reactome pathways

127 total, by targets touching each:

Pathway	Targets	Genes
Apoptosis	3	AKT1, AKT2, AKT3
Intrinsic Pathway for Apoptosis	3	AKT1, AKT2, AKT3
Activation of BAD and translocation to mitochondria	3	AKT1, AKT2, AKT3
Activation of BH3-only proteins	3	AKT1, AKT2, AKT3
Signaling by ERBB2	3	AKT1, AKT2, AKT3
PIP3 activates AKT signaling	3	AKT1, AKT2, AKT3
Developmental Biology	3	AKT1, AKT2, AKT3
Cytokine Signaling in Immune system	3	AKT1, AKT2, AKT3
Adaptive Immune System	3	AKT1, AKT2, AKT3
Downregulation of ERBB2:ERBB3 signaling	3	AKT1, AKT2, AKT3
Signal Transduction	3	AKT1, AKT2, AKT3
Cell Cycle	3	AKT1, AKT2, AKT3
Disease	3	AKT1, AKT2, AKT3
MTOR signalling	3	AKT1, AKT2, AKT3
Inhibition of TSC complex formation by AKT (PKB)	3	AKT1, AKT2, AKT3
Immune System	3	AKT1, AKT2, AKT3
Regulation of beta-cell development	3	AKT1, AKT2, AKT3
Signaling by VEGF	3	AKT1, AKT2, AKT3
AKT phosphorylates targets in the cytosol	3	AKT1, AKT2, AKT3
AKT phosphorylates targets in the nucleus	3	AKT1, AKT2, AKT3
Negative regulation of the PI3K/AKT network	3	AKT1, AKT2, AKT3
Membrane Trafficking	3	AKT1, AKT2, AKT3
Regulation of gene expression in beta cells	3	AKT1, AKT2, AKT3
AKT-mediated inactivation of FOXO1A	3	AKT1, AKT2, AKT3
Generic Transcription Pathway	3	AKT1, AKT2, AKT3
PI3K/AKT Signaling in Cancer	3	AKT1, AKT2, AKT3
Cellular responses to stress	3	AKT1, AKT2, AKT3
Transcriptional Regulation by TP53	3	AKT1, AKT2, AKT3
Signaling by GPCR	3	AKT1, AKT2, AKT3
GPCR downstream signalling	3	AKT1, AKT2, AKT3

Dominant GO biological processes

GO term	Targets
protein phosphorylation	3
signal transduction	3
insulin receptor signaling pathway	3
positive regulation of cell migration	3
intracellular signal transduction	3
negative regulation of apoptotic process	3
positive regulation of blood vessel endothelial cell migration	3
negative regulation of PERK-mediated unfolded protein response	3
positive regulation of endothelial cell proliferation	2
glycogen biosynthetic process	2
glucose metabolic process	2
regulation of translation	2
negative regulation of long-chain fatty acid import across plasma membrane	2
positive regulation of glucose metabolic process	2
regulation of cell migration	2

Indications & clinical

Indications

7 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
breast neoplasm	3	MONDO:0021100	MONDO:0007254
Langerhans cell histiocytosis	2	MONDO:0018310	EFO:1000318
ovarian cancer	2	MONDO:0008170	MONDO:0008170
neoplasm	1	MONDO:0005070	EFO:0000616
plasma cell myeloma	1	MONDO:0009693	EFO:0001378

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

Clinical trials

Total trials: 12.

Phase distribution

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

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04851613	PHASE3	ACTIVE_NOT_RECRUITING	Study to Evaluate Efficacy & Safety of Afuresertib Plus Fulvestrant in Patients With Locally Advanced or Metastatic HR+/HER2- Breast Cancer
NCT01395004	PHASE2	COMPLETED	A Study to Test the Ability of and Safety of GSK2110183 in Treating Langerhans Cell Histiocytosis
NCT01531894	PHASE2	COMPLETED	Continuation Study of the Oral AKT Inhibitor GSK2110183
NCT04374630	PHASE2	COMPLETED	Study With Afuresertib and Paclitaxel in Platinum Resistant Ovarian
NCT05383482	PHASE1/PHASE2	COMPLETED	Afuresertib +Sintilimab+Chemotherapy in Patients With Selected Solid Tumors That Resistance to Prior Anti-PD-1/PD-L1
NCT01428492	PHASE1	COMPLETED	Ph 1b Study to Evaluate GSK2110183 in Combination With Bortezomib and Dexamethasone in Subjects With Multiple Myeloma
NCT01476137	PHASE1	COMPLETED	A Study of the Safety and Activity of the MEK Inhibitor Given Together With the AKT Inhibitor to Patients With Multiple Myeloma or Solid Tumor Cancers
NCT02177682	PHASE1	TERMINATED	Study of Afuresertib Monotherapy in Japanese Relapsed Multiple Myeloma Patients
NCT02235740	PHASE1	TERMINATED	A Study Conducted in Subjects With Relapsed/Refractory Multiple Myeloma (MM); to Determine Dose of Afuresertib in Combination With Carfilzomib (Part 1) and to Investigate the Safety, Pharmacokinetic and Clinical Activity of the Combination Compared With Carfilzomib Alone (Part 2)
NCT02240212	PHASE1	COMPLETED	Study of Afuresertib Combined With Paclitaxel in Gastric Cancer
NCT02380313	PHASE1	WITHDRAWN	Dose-Finding Study of Afuresertib Administered in Combination With Either Enzalutamide or Aibraterone
NCT05390710	PHASE1	COMPLETED	PhI to Solid Tumors and PhII to Locally Advanced or mTNBC

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.

41 molecules share ≥1 primary target. Top 41 by shared-target count:

Molecule	Source	Status	Shared targets
CAPIVASERTIB	ChEMBL	Phase 4 (approved)	AKT1, AKT2, AKT3
MIDOSTAURIN	ChEMBL	Phase 4 (approved)	AKT1, AKT2, AKT3
IPATASERTIB	ChEMBL	Phase 3	AKT1, AKT2, AKT3
LESTAURTINIB	ChEMBL	Phase 3	AKT1, AKT2, AKT3
MIRANSERTIB	ChEMBL	Phase 2	AKT1, AKT2, AKT3
MK-2206	ChEMBL	Phase 2	AKT1, AKT2, AKT3
UPROSERTIB	ChEMBL	Phase 2	AKT1, AKT2, AKT3
Afatinib	PubChem	Approved	AKT1, AKT2, AKT3
belumosudil	PubChem	Approved	AKT1, AKT2, AKT3
Binimetinib	PubChem	Approved	AKT1, AKT2, AKT3
Crizotinib	PubChem	Approved	AKT1, AKT2, AKT3
dacomitinib	PubChem	Approved	AKT1, AKT2, AKT3
Fostamatinib	PubChem	Approved	AKT1, AKT2, AKT3
Idelalisib	PubChem	Approved	AKT1, AKT2, AKT3
Pazopanib	PubChem	Approved	AKT1, AKT2, AKT3
regorafenib	PubChem	Approved	AKT1, AKT2, AKT3
Selumetinib	PubChem	Approved	AKT1, AKT2, AKT3
Trametinib	PubChem	Approved	AKT1, AKT2, AKT3
FASUDIL	ChEMBL	Phase 3	AKT1, AKT3
RUBOXISTAURIN	ChEMBL	Phase 3	AKT2, AKT3
LAUROGUADINE	ChEMBL	Phase 2	AKT1, AKT2
SOTRASTAURIN	ChEMBL	Phase 2	AKT1, AKT2
Gefitinib	PubChem	Approved	AKT2, AKT3
MILTEFOSINE	ChEMBL	Phase 4 (approved)	AKT1
NICLOSAMIDE	ChEMBL	Phase 4 (approved)	AKT1
SUNITINIB	ChEMBL	Phase 4 (approved)	AKT2
ENZASTAURIN	ChEMBL	Phase 3	AKT3
LINIFANIB	ChEMBL	Phase 3	AKT1
PERIFOSINE	ChEMBL	Phase 3	AKT1
QUERCETIN	ChEMBL	Phase 3	AKT1
EDELFOSINE	ChEMBL	Phase 2	AKT1
ELLAGIC ACID	ChEMBL	Phase 2	AKT1
KALAFUNGIN	ChEMBL	Phase 2	AKT1
PF-04691502	ChEMBL	Phase 2	AKT1
PICTILISIB	ChEMBL	Phase 2	AKT1
RUPITASERTIB	ChEMBL	Phase 2	AKT1
SULFAETHIDOLE	ChEMBL	Phase 2	AKT1
Belzutifan	PubChem	Approved	AKT2
Cobimetinib	PubChem	Approved	AKT3
Fedratinib	PubChem	Approved	AKT3
podofilox	PubChem	Approved	AKT1