Osugacestat

Investigational

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

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	MOL RATIO 1 MOL RATIO (average)

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

Description

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	Inhibitor 8,297	1.6 nM [IC50]
Neurogenic locus notch homolog protein 2 1	Inhibitor 8,297	0.7 nM [IC50]
Neurogenic locus notch homolog protein 3 1	Inhibitor 8,297	3.4 nM [IC50]
Neurogenic locus notch homolog protein 4 1	Inhibitor 8,297	2.9 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Cancer 592	Primary		Phase I 428	Unknown
Acute T-cell lymphoblastic leukemia 1	Primary		Phase I 428	Unknown

C_max

Value	Dose	Analyte	Population
754 μg/mL	30 mg/kg single, intravenous	BMS-906024 serum	Homo sapiens
14.3 μg/mL	300 mg single, subcutaneous	BMS-906024 serum	Homo sapiens
782 μg/mL	30 mg/kg 1 times / 4 weeks steady-state, intravenous	BMS-906024 serum	Homo sapiens
19.5 μg/mL	300 mg 1 times / 2 weeks multiple, subcutaneous	BMS-906024 serum	Homo sapiens
155 μg/mL	6 mg/kg single, intravenous	BMS-906024 serum	Homo sapiens
372 μg/mL	15 mg/kg single, intravenous	BMS-906024 serum	Homo sapiens
753 μg/mL	30 mg/kg single, intravenous	BMS-906024 serum	Homo sapiens
1740 μg/mL	60 mg/kg single, intravenous	BMS-906024 serum	Homo sapiens
48 μg/mL	600 mg single, subcutaneous	BMS-906024 serum	Homo sapiens

AUC

Value	Dose	Analyte	Population
179000 μg × h/mL	30 mg/kg single, intravenous	BMS-906024 serum	Homo sapiens
3530 μg × h/mL	300 mg single, subcutaneous	BMS-906024 serum	Homo sapiens
262000 μg × h/mL	30 mg/kg 1 times / 4 weeks steady-state, intravenous	BMS-906024 serum	Homo sapiens
10600 μg × h/mL	300 mg 1 times / 2 weeks multiple, subcutaneous	BMS-906024 serum	Homo sapiens
18700 μg × h/mL	6 mg/kg single, intravenous	BMS-906024 serum	Homo sapiens
74400 μg × h/mL	15 mg/kg single, intravenous	BMS-906024 serum	Homo sapiens
178000 μg × h/mL	30 mg/kg single, intravenous	BMS-906024 serum	Homo sapiens
438000 μg × h/mL	60 mg/kg single, intravenous	BMS-906024 serum	Homo sapiens
13500 μg × h/mL	600 mg single, subcutaneous	BMS-906024 serum	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
215 h	30 mg/kg single, intravenous	BMS-906024 serum	Homo sapiens
93.8 h	300 mg single, subcutaneous	BMS-906024 serum	Homo sapiens
296 h	30 mg/kg 1 times / 4 weeks steady-state, intravenous	BMS-906024 serum	Homo sapiens
79 h	300 mg 1 times / 2 weeks multiple, subcutaneous	BMS-906024 serum	Homo sapiens
83.2 h	6 mg/kg single, intravenous	BMS-906024 serum	Homo sapiens
196 h	15 mg/kg single, intravenous	BMS-906024 serum	Homo sapiens
261 h	30 mg/kg single, intravenous	BMS-906024 serum	Homo sapiens
294 h	60 mg/kg single, intravenous	BMS-906024 serum	Homo sapiens
95.8 h	600 mg single, subcutaneous	BMS-906024 serum	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
11.3%	10 μmol single, intravenous		BMS-906024 plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
8.4 mg 1 times / week multiple, intravenous Highest studied dose	unhealthy, ADULT	DLT: Infusion reaction, Vomiting...
4 mg 1 times / week multiple, intravenous MTD	unhealthy, ADULT
6 mg 1 times / 2 weeks multiple, intravenous MTD	unhealthy, ADULT	DLT: Diarrhea...

Showing 1 to 3 of 3 entries

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AEs

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AE	Significance	Dose	Population
Infusion reaction	grade 3, 14.3% DLT	8.4 mg 1 times / week multiple, intravenous Highest studied dose	unhealthy, ADULT
Vomiting	grade 3, 14.3% DLT	8.4 mg 1 times / week multiple, intravenous Highest studied dose	unhealthy, ADULT
Liver failure	grade 5, 14.3% DLT, Disc. AE	8.4 mg 1 times / week multiple, intravenous Highest studied dose	unhealthy, ADULT
Diarrhea	grade 3, 16.7% DLT	6 mg 1 times / 2 weeks multiple, intravenous MTD	unhealthy, ADULT

Showing 1 to 4 of 4 entries

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	HLM 31

Drug as victim

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Target	Modality	Activity	Metabolite	Clinical evidence
HLM 31	substrate 3,367	no [Inhibition 0.5 uM]

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Sourcing

Sourcing

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

PubMed

Title	Date	PubMed
No data available in table

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
Record UNII	DRL23N424R
Record Status	`Validated (UNII)`
Record Version

Show entries

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

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Classification Tree

Code System

Code

Designated

FDA ORPHAN DRUG

683819

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Code System

Code

Type

Description

INN

11648

PRIMARY

INN

USAN

JK-36

PRIMARY

EPA CompTox

DTXSID30161234

PRIMARY

DRUG BANK

DB12006

PRIMARY

WIKIPEDIA

BMS-906024

PRIMARY

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Related Record

Type

Details


					Q0AJ4B9B5N

NEUROGENIC LOCUS NOTCH HOMOLOG PROTEIN 3 (HUMAN)

TARGET -> INHIBITOR

Amount:

3.4 NANOMOLAR (average)


					Q0AJ4B9B5N

NEUROGENIC LOCUS NOTCH HOMOLOG PROTEIN 3 (HUMAN)

TARGET -> INHIBITOR

Qualification:

IC50

Amount:

3.4 (average)


					2GWO8DN9N6

NEUROGENIC LOCUS NOTCH HOMOLOG PROTEIN 2

TARGET -> INHIBITOR

Qualification:

IC50

Amount:

0.7 NANOMOLAR (average)


					9372WZW6L3

.GAMMA.-SECRETASE

TARGET -> INHIBITOR

Amount:


					PE35I3T5TN

NEUROGENIC LOCUS NOTCH HOMOLOG PROTEIN 1

TARGET -> INHIBITOR

Qualification:

IC50

Amount:

1.6 NANOMOLAR (average)

Showing 1 to 5 of 5 entries

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Related Record

Type

Details


					DRL23N424R

Osugacestat

ACTIVE MOIETY

Amount:

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SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as victim

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound