Osugacestat

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C26H26F6N4O3
Molecular Weight	556.5001
Optical Activity	( - )
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN1C2=CC=CC=C2C(=N[C@H](NC(=O)[C@H](CCC(F)(F)F)[C@H](CCC(F)(F)F)C(N)=O)C1=O)C3=CC=CC=C3

InChI

InChIKey=AYOUDDAETNMCBW-GSHUGGBRSA-N

InChI=1S/C26H26F6N4O3/c1-36-19-10-6-5-9-18(19)20(15-7-3-2-4-8-15)34-22(24(36)39)35-23(38)17(12-14-26(30,31)32)16(21(33)37)11-13-25(27,28)29/h2-10,16-17,22H,11-14H2,1H3,(H2,33,37)(H,35,38)/t16-,17+,22+/m0/s1

HIDE SMILES / InChI

Molecular Formula	C26H26F6N4O3
Molecular Weight	556.5001
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	3 / 3
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26005526 | https://www.denovodata.com/pipeline/bristol-myers-squibb-leukemia/

BMS-906024 is a lead candidate of a series of inhibitors of gamma secretase-mediated Notch signalling. BMS-906024 is an orally bioavailable, small-molecule gamma secretase (GS) and pan-Notch inhibitor, with potential antineoplastic activity. Upon administration, GS/pan-Notch inhibitor BMS-906024 binds to GS and blocks activation of Notch receptors, which may inhibit the proliferation of tumor cells with an overly-active Notch pathway. The integral membrane protein GS is a multi-subunit protease complex that cleaves single-pass transmembrane proteins, such as Notch receptors, at residues within their transmembrane domains that lead to their activation. Overexpression of the Notch signaling pathway has been correlated with increased tumor cell growth. BMS-906024 is currently in Phase 1 clinical trials for patients with T-cell acute lymphoblastic leukemia and metastatic solid tumors, including lung cancer.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Neurogenic locus notch homolog protein 1 1 Target ID: CHEMBL2146346 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26005526	Inhibitor 8297	1.6 nM [IC50]
Neurogenic locus notch homolog protein 2 1 Target ID: CHEMBL3407320 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26005526	Inhibitor 8297	0.7 nM [IC50]
Neurogenic locus notch homolog protein 3 1 Target ID: CHEMBL3407319 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26005526	Inhibitor 8297	3.4 nM [IC50]
Neurogenic locus notch homolog protein 4 1 Target ID: CHEMBL3407321 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26005526	Inhibitor 8297	2.9 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Cancer 592 Sources: https://clinicaltrials.gov/ct2/show/NCT01292655 http://adisinsight.springer.com/drugs/800034062	Primary		Phase I 428	Unknown Approved Use Unknown
Acute T-cell lymphoblastic leukemia 1 Sources: https://clinicaltrials.gov/ct2/show/NCT01363817	Primary		Phase I 428	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
0.3 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26005526	1 mg/kg single, oral dose: 1 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		BMS-906024 plasma	Mus musculus population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
1 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26005526	1 mg/kg single, intravenous dose: 1 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		BMS-906024 plasma	Mus musculus population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
1.9 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26005526	1 mg/kg single, oral dose: 1 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		BMS-906024 plasma	Mus musculus population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
3.4 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26005526	1 mg/kg single, intravenous dose: 1 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		BMS-906024 plasma	Mus musculus population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
5.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26005526	1 mg/kg single, oral dose: 1 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		BMS-906024 plasma	Mus musculus population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
4.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26005526	1 mg/kg single, intravenous dose: 1 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		BMS-906024 plasma	Mus musculus population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
4.1% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26005526	1 mg/kg single, oral dose: 1 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		BMS-906024 plasma	Mus musculus population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
4.1% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26005526	1 mg/kg single, intravenous dose: 1 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		BMS-906024 plasma	Mus musculus population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
8.4 mg 1 times / week multiple, intravenous Highest studied dose Dose: 8.4 mg, 1 times / week Route: intravenous Route: multiple Dose: 8.4 mg, 1 times / week Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.2515	unhealthy, ADULT n = 7 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.2515	DLT: Infusion reaction, Liver failure... Dose limiting toxicities: Infusion reaction (grade 3, 14.3%) Liver failure (grade 5, 14.3%) Vomiting (grade 3, 14.3%) Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.2515
4 mg 1 times / week multiple, intravenous MTD Dose: 4 mg, 1 times / week Route: intravenous Route: multiple Dose: 4 mg, 1 times / week Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.2515	unhealthy, ADULT n = 7 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.2515	Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.2515
6 mg 1 times / 2 weeks multiple, intravenous MTD Dose: 6 mg, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 6 mg, 1 times / 2 weeks Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.2515	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.2515	DLT: Diarrhea... Dose limiting toxicities: Diarrhea (grade 3, 16.7%) Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.2515

AEs

AE	Significance	Dose	Population
Infusion reaction	grade 3, 14.3% DLT	8.4 mg 1 times / week multiple, intravenous Highest studied dose Dose: 8.4 mg, 1 times / week Route: intravenous Route: multiple Dose: 8.4 mg, 1 times / week Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.2515	unhealthy, ADULT n = 7 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.2515
Vomiting	grade 3, 14.3% DLT	8.4 mg 1 times / week multiple, intravenous Highest studied dose Dose: 8.4 mg, 1 times / week Route: intravenous Route: multiple Dose: 8.4 mg, 1 times / week Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.2515	unhealthy, ADULT n = 7 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.2515
Liver failure	grade 5, 14.3% DLT, Disc. AE	8.4 mg 1 times / week multiple, intravenous Highest studied dose Dose: 8.4 mg, 1 times / week Route: intravenous Route: multiple Dose: 8.4 mg, 1 times / week Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.2515	unhealthy, ADULT n = 7 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.2515
Diarrhea	grade 3, 16.7% DLT	6 mg 1 times / 2 weeks multiple, intravenous MTD Dose: 6 mg, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 6 mg, 1 times / 2 weeks Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.2515	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.2515

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	HLM 31

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
HLM 31	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/26005526/	no [Inhibition 0.5 uM]

Sourcing

Vendor/Aggregator	ID	URL
AstaTech	93506	http://astatechinc.com/CPSResult.php?CRNO=93506
Norris Pharm	NSZB-A218544

PubMed

Title	Date	PubMed
Discovery of Clinical Candidate BMS-906024: A Potent Pan-Notch Inhibitor for the Treatment of Leukemia and Solid Tumors.	2015 May 14	26005526
Complete hematologic response of early T-cell progenitor acute lymphoblastic leukemia to the γ-secretase inhibitor BMS-906024: genetic and epigenetic findings in an outlier case.	2015 Oct	27148573
Gamma Secretase Inhibition by BMS-906024 Enhances Efficacy of Paclitaxel in Lung Adenocarcinoma.	2017 Dec	28978720

Patents

Sample Use Guides

In Vivo Use Guide

BMS-906024 escalating doses starting at 0.3 mg solution for intravenous (IV) administration once weekly continuously until disease progression or unacceptable toxicity.

Route of Administration: Intravenous

In Vitro Use Guide

BMS-906024 reduced Notch1 ICD levels in all six lung cancer cell lines tested at concentrations as low as 5 nM, with maximal depletion at 50 -100 nM.

Substance Class	Chemical Created by `admin` on `Sat Dec 16 06:11:23 GMT 2023` Edited by `admin` on `Sat Dec 16 06:11:23 GMT 2023`
Record UNII	DRL23N424R
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

Osugacestat

Official Name

English

AL101

Code

English

BMS 906024 [WHO-DD]

Common Name

English

OSUGACESTAT [USAN]

Common Name

English

Butanediamide, N1-[(3S)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)-, (2R,3S)-

Systematic Name

English

osugacestat [INN]

Common Name

English

BM-0018

Code

English

BM0018

Code

English

AL-101

Code

English

BMS-906024

Code

English

(2R,3S)-N-((3S)-1-Methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide

Systematic Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

683819