Suite of Biochemical and Cell-Based Assays for the Characterization of Kirsten Rat Sarcoma (KRAS) Inhibitors and Degraders.

Autor:	Kidane M; Research and Development and Technology Transfer, Eurofins DiscoverX, LLC, 11180 Roselle Street Suite D, San Diego, California 92121, United States., Hoffman RM; Research and Development, Eurofins DiscoverX Products, LLC, 42501 Albrae Street, Fremont, California 94538, United States., Wolfe-Demarco JK; Research and Development and Technology Transfer, Eurofins DiscoverX, LLC, 11180 Roselle Street Suite D, San Diego, California 92121, United States., Huang TY; Eurofins Panlabs Discovery Services Taiwan, Ltd., 25 Wugong Sixth Road, Wugu District, New Taipei City 24891, Taiwan., Teng CL; Eurofins Panlabs Discovery Services Taiwan, Ltd., 25 Wugong Sixth Road, Wugu District, New Taipei City 24891, Taiwan., Samanta S; Research and Development, Eurofins DiscoverX Products, LLC, 42501 Albrae Street, Fremont, California 94538, United States., Gonzalez Lira LM; Research and Development and Technology Transfer, Eurofins DiscoverX, LLC, 11180 Roselle Street Suite D, San Diego, California 92121, United States., Lin-Jones J; Research and Development, Eurofins DiscoverX Products, LLC, 42501 Albrae Street, Fremont, California 94538, United States., Pallares G; Research and Development and Technology Transfer, Eurofins DiscoverX, LLC, 11180 Roselle Street Suite D, San Diego, California 92121, United States., Lamerdin JE; Research and Development, Eurofins DiscoverX Products, LLC, 42501 Albrae Street, Fremont, California 94538, United States., Servant NB; Research and Development and Technology Transfer, Eurofins DiscoverX, LLC, 11180 Roselle Street Suite D, San Diego, California 92121, United States., Lee CY; Eurofins Panlabs Discovery Services Taiwan, Ltd., 25 Wugong Sixth Road, Wugu District, New Taipei City 24891, Taiwan., Yang CT; Research and Development, Eurofins DiscoverX Products, LLC, 42501 Albrae Street, Fremont, California 94538, United States., Bernatchez JA; Research and Development and Technology Transfer, Eurofins DiscoverX, LLC, 11180 Roselle Street Suite D, San Diego, California 92121, United States.
Jazyk:	angličtina
Zdroj:	ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2024 Dec 02; Vol. 7 (12), pp. 3921-3934. Date of Electronic Publication: 2024 Dec 02 (Print Publication: 2024).
DOI:	10.1021/acsptsci.4c00450
Abstrakt:	KRAS is an important oncogenic driver which is mutated in numerous cancers. Recent advances in the selective targeting of KRAS mutants via small molecule inhibitors and targeted protein degraders have generated an increase in research activity in this area in recent years. As such, there is a need for new assay platforms to profile next generation inhibitors which improve on the potency and selectivity of existing drug candidates, while evading the emergence of resistance. Here, we describe the development of a new panel of biochemical and cell-based assays to evaluate the binding and function of known chemical entities targeting mutant KRAS. Our assay panels generated selectivity profiles and quantitative binding interaction dissociation constants for small molecules and degraders against wild type, G12C, G12D, and G12V KRAS, which were congruent with published data. These assays can be leveraged for additional mutants of interest beyond those described in this study, using both overexpressed cell-free systems and cell-based systems with endogenous protein levels. Competing Interests: The authors declare the following competing financial interest(s): This work was supported by Eurofins DiscoverX, LLC, Eurofins DiscoverX Products, LLC, and Eurofins Panlabs Discovery Services Taiwan, Ltd. M.K., J.K.W.D., L.M.G.L., G.P., N.B.S., and J.A.B. are employees of Eurofins DiscoverX, LLC. R.M.H, S.S., J.L.J., J.E.L., and C.T.Y. are employees of Eurofins DiscoverX Products, LLC. T.Y.H., C.L.T., and C.Y.L. are employees of Eurofins Panlabs Discovery Services Taiwan, Ltd. (© 2024 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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