Adagrasib

CovInDB Drug

DB15568

Name

Adagrasib

Molecular Formula

C32H35ClFN7O2

Molecular Weight

603.2525 g/mol

Description

Adagrasib is a KRAS inhibitor indicated for the treatment of locally advanced or metastatic KRAS G12C-mutated non-small cell lung cancer in patients who have received at least one prior systemic therapy.

Status

approved, investigational

Structure

  Warhead   Similar Compounds

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SDF 2D SDF 3D

Indication

Adagrasib is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy. This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s).

Mechanism of action

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In normal cells, KRAS is activated by binding to guanosine triphosphate (GTP), and this promotes the activation of the MAP kinase pathway and intracellular signal transduction. When GTP is hydrolyzed to guanosine diphosphate (GDP), KRAS is inactivated. This mechanism works as an "on"/"off" system that regulates cell growth. The substitution of Gly12 by cysteine in KRAS (KRASG12C) impairs GTP hydrolysis, and maintains KRAS in its active form. Therefore, the presence of this mutation leads to uncontrolled cellular proliferation and growth, as well as malignant transformation. Adagrasib is a covalent inhibitor of KRASG12C that irreversibly and selectively binds and locks KRASG12C in its inactive, guanosine diphosphate–bound state. Therefore, the use of adagrasib inhibits tumor cell growth and viability in cancers with KRASG12C mutations with minimal off-target activity.

IUPAC Name

2-[(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

InChI

InChI=1S/C32H35ClFN7O2/c1-21(34)31(42)41-17-16-40(18-23(41)11-13-35)30-25-12-15-39(28-10-4-7-22-6-3-9-26(33)29(22)28)19-27(25)36-32(37-30)43-20-24-8-5-14-38(24)2/h3-4,6-7,9-10,23-24H,1,5,8,11-12,14-20H2,2H3/t23-,24-/m0/s1

InChI Key

PEMUGDMSUDYLHU-ZEQRLZLVSA-N

Canonical SMILES

[H][C@@]1(COC2=NC3=C(CCN(C3)C3=CC=CC4=C3C(Cl)=CC=C4)C(=N2)N2CCN(C(=O)C(F)=C)[C@@]([H])(CC#N)C2)CCCN1C

Reference

DrugBank

Warhead

Micheal Acceptor

Target

GTPase KRas   [ UniProt: P01116 ]

Site

CYS-12

Inhibition Mechanism

The KRASG12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancers in Mouse Models and Patients.

logP

5.16

Computed by ALOGPS

logS

-4.72

Computed by ALOGPS

Heavy Atom Count

43

Computed by RDKit

Ring Count

6

Computed by RDKit

Hydrogen Bond Acceptor Count

8

Computed by RDKit

Hydrogen Bond Donor Count

0

Computed by RDKit

Rotatable Bond Count

7

Computed by RDKit

Topological Polar Surface Area

88.83 Ų

Computed by RDKit

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No similar natural compounds found for this drug.