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. 2020 Jul 9;63(13):6677-6678.
doi: 10.1021/acs.jmedchem.0c00785. Epub 2020 Jun 22.

Hitting KRAS When It's Down

Ronen Gabizon  1 , Nir London  1
Affiliations

Hitting KRAS When It's Down

Ronen Gabizon et al. J Med Chem. .

Abstract

KRAS, one of the most prevalent oncogenes and sought-after anticancer targets, has eluded chemists for decades until an irreversible covalent strategy targeting a specific mutation (G12C) paved the way for the first KRAS inhibitors to reach the clinic. MRTX849 is one such clinical candidate with promising initial results in patients harboring the mutation. The impressive optimization story of MRTX849 highlights challenges and solutions in the development of covalent drugs, including the use of an α-fluoroacrylamide electrophile.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structures and optimization of clinical covalent KRASG12C inhibitors. (A) Chemical structures of advanced KRASG12C inhibitors. Highlighted in red is the almost identical scaffold shared by all three major series. Compound 4 previously reported by Fell et al. was progressed to compound 13 that suffered from clearance problems. Now, compound 13 was optimized to the clinical compound MRTX849. Red and blue arrows indicate improvement or deterioration in potency and PK/PD, respectively, for each modification introduced. (B) Cocrystal structures of KRASG12C in complex with the various binders show the highly similar binding modes of these compounds. No structure is available for compound 13; however a very close analog (compound 12(5)) illustrates the changes in interactions with the protein achieved by the introduced modifications. PDB codes from left to right are the following: 5V9U, 6OIM, 6N2J, 6N2K, 6UT0.
See this image and copyright information in PMC

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