divarasib   Click here for help

GtoPdb Ligand ID: 11963

Synonyms: GDC-6036 | GDC6036 | RG-6330 | RG6330
Compound class: Synthetic organic
Comment: GDC-6036 is an oral, covalent inhibitor that targets oncogenic KRASG12C [2-3]. Inhibitor binding locks KRASG12C into its inactive GDP-bound state. GDC-6036's chemical structure was revealed at the AACR spring meeting in 2022. The structure is claimed i patent US11236068B2 [1], and [3] provides the chemical name 1-((S)-4-((R)-7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (adipiate salt). We matched GDC-6036's chemical structure to the INN 'divarasib' which was published in the WHO's proposed INN list 127 on 21 July 2022.
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species

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2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 8
Hydrogen bond donors 1
Rotatable bonds 8
Topological polar surface area 100.71
Molecular weight 621.22
XLogP 6.2
No. Lipinski's rules broken 1

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES C=CC(=O)N1CCN([C@H](C1)C)c1nc(OC[C@@H]2CCCN2C)nc2c1cc(Cl)c(c2F)c1nc(N)cc(c1C(F)(F)F)C
Isomeric SMILES C[C@H]1CN(CCN1c1c2cc(Cl)c(c(F)c2nc(OC[C@@H]2CCCN2C)n1)c1c(c(C)cc(N)n1)C(F)(F)F)C(=O)C=C
InChI InChI=1S/C29H32ClF4N7O2/c1-5-21(42)40-9-10-41(16(3)13-40)27-18-12-19(30)22(26-23(29(32,33)34)15(2)11-20(35)36-26)24(31)25(18)37-28(38-27)43-14-17-7-6-8-39(17)4/h5,11-12,16-17H,1,6-10,13-14H2,2-4H3,(H2,35,36)/t16-,17-/m0/s1
InChI Key ZRBPIAWWRPFDPY-IRXDYDNUSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
References
1. Malhotra S, Xin J, Do S, Terrett J. (2022)
Fused ring compounds.
Patent number: US11236068B2. Assignee: Pharmaron, Hoffmann La Foche (originally Genentech). Priority date: 09/11/2018. Publication date: 01/02/2022.
2. Meng L, Chan EW, Ng C, Aimi J, Tran JC, Oh AJ, Merchant M, Purkey HE, Heffron TP, Kaur S et al.. (2022)
Assessment of KRAS G12C Target Engagement by a Covalent Inhibitor in Tumor Biopsies Using an Ultra-Sensitive Immunoaffinity 2D-LC-MS/MS Approach.
Anal Chem, 94 (37): 12927-12933. [PMID:36083155]
3. Xu J, Grosslight S, Mack KA, Nguyen SC, Clagg K, Lim NK, Timmerman JC, Shen J, White NA, Sirois LE et al.. (2022)
Atroposelective Negishi Coupling Optimization Guided by Multivariate Linear Regression Analysis: Asymmetric Synthesis of KRAS G12C Covalent Inhibitor GDC-6036.
J Am Chem Soc, 144 (45): 20955-20963. [PMID:36326518]