Discovery of PF-06873600, a CDK2/4/6 Inhibitor for the Treatment of Cancer.

Autor:	Freeman-Cook KD; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Hoffman RL; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Behenna DC; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Boras B; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Carelli J; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Diehl W; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Ferre RA; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., He YA; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Hui A; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Huang B; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Huser N; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Jones R; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Kephart SE; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Lapek J; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., McTigue M; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Miller N; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Murray BW; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Nagata A; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Nguyen L; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Niessen S; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Ninkovic S; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., O'Doherty I; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Ornelas MA; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Solowiej J; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Sutton SC; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Tran K; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Tseng E; Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States., Visswanathan R; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Xu M; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Zehnder L; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Zhang Q; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Zhang C; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States., Dann S; Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2021 Jul 08; Vol. 64 (13), pp. 9056-9077. Date of Electronic Publication: 2021 Jun 10.
DOI:	10.1021/acs.jmedchem.1c00159
Abstrakt:	Control of the cell cycle through selective pharmacological inhibition of CDK4/6 has proven beneficial in the treatment of breast cancer. Extending this level of control to additional cell cycle CDK isoforms represents an opportunity to expand to additional tumor types and potentially provide benefits to patients that develop tumors resistant to selective CDK4/6 inhibitors. However, broad-spectrum CDK inhibitors have a long history of failure due to safety concerns. In this approach, we describe the use of structure-based drug design and Free-Wilson analysis to optimize a series of CDK2/4/6 inhibitors. Further, we detail the use of molecular dynamics simulations to provide insights into the basis for selectivity against CDK9. Based on overall potency, selectivity, and ADME profile, PF-06873600 ( 22 ) was identified as a candidate for the treatment of cancer and advanced to phase 1 clinical trials.
Databáze:	MEDLINE
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