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Synfacts 2023; 19(02): 0189
DOI: 10.1055/s-0042-1753239
Innovative Drug Discovery and Development

Multivariate Linear Regression Informs Ligand Design to Improve the Synthesis of a KRAS Inhibitor

Contributor(s):
Antonia F. Stepan (Roche)
,
Nadine Kuhl (MSD)
Zhang H, *, Sigman MS. * et al. Genentech, Inc., South San Francisco and University of Utah, Salt Lake City, USA
Atroposelective Negishi Coupling Optimization Guided by Multivariate Linear Regression Analysis: Asymmetric Synthesis of KRAS G12C Covalent Inhibitor GDC-6036.

J. Am. Chem. Soc. 2022;
144: 20955-20963
DOI: 10.1021/jacs.2c09917.
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Key words

Negishi coupling - axial chirality - multivariate linear regression - process chemistry

Significance

KRAS, a frequently mutated oncogene, has been linked to the progression of various cancers and is therefore pursued as an anticancer target. Genentech has recently developed GDC-6036, an irreversible covalent inhibitor of the KRAS G12C mutation which features an axial chiral pyridine–quinazoline biaryl moiety that poses a significant synthetic challenge.


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Comment

Utilizing high-throughput experimentation, the Walphos ligand class was found to yield biaryl intermediate C via a Negishi coupling as either (R)- or (S)-atropisomer with moderate er values. However, no intuitive structure–selectivity trends of the ligands tested could be identified. Therefore, multivariate linear regression (MLR) analysis was employed which successfully predicted ligand D to be more selective. Using D, desired (R a)-C was obtained with er = 98:2 and could be further elaborated to GDC-6036.


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Publication History

Article published online:
17 January 2023

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