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

被引：64

作者：

Freeman-Cook, Kevin D. ^{[1
]}

Hoffman, Robert L. ^{[1
]}

Behenna, Douglas C. ^{[1
]}

Boras, Britton ^{[1
]}

Carelli, Jordan ^{[1
]}

Diehl, Wade ^{[1
]}

Ferre, Rose Ann ^{[1
]}

He, You-Ai ^{[1
]}

Hui, Andrea ^{[1
]}

Huang, Buwen ^{[1
]}

Huser, Nanni ^{[1
]}

Jones, Rhys ^{[1
]}

Kephart, Susan E. ^{[1
]}

Lapek, John ^{[1
]}

McTigue, Michele ^{[1
]}

Miller, Nichol ^{[1
]}

Murray, Brion W. ^{[1
]}

Nagata, Asako ^{[1
]}

Nguyen, Lisa ^{[1
]}

Niessen, Sherry ^{[1
]}

Ninkovic, Sacha ^{[1
]}

O'Doherty, Inish ^{[1
]}

Ornelas, Martha A. ^{[1
]}

Solowiej, James ^{[1
]}

Sutton, Scott C. ^{[1
]}

Tran, Khanh ^{[1
]}

Tseng, Elaine ^{[2
]}

Visswanathan, Ravi ^{[1
]}

Xu, Meirong ^{[1
]}

Zehnder, Luke ^{[1
]}

Zhang, Qin ^{[1
]}

Zhang, Cathy ^{[1
]}

Dann, Stephen ^{[1
]}

机构：

[1] Pfizer Global Res & Dev La Jolla, San Diego, CA 92121 USA

[2] Pfizer Global Res & Dev, Groton, CT 06340 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 13期

关键词：

DEPENDENT KINASE INHIBITOR; CELL-CYCLE; LIPOPHILIC EFFICIENCY; PHOSPHORYLATION; FLAVOPIRIDOL; RESISTANCE; PROLIFERATION; CARCINOMA; TARGET; GROWTH;

D O I：

10.1021/acs.jmedchem.1c00159

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：9056 / 9077

页数：22

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