jm9b02121_si_001.pdf (11.03 MB)
Discovery and SARs of 5‑Chloro‑N4‑phenyl‑N2‑(pyridin-2-yl)pyrimidine-2,4-diamine Derivatives as Oral Available and Dual CDK 6 and 9 Inhibitors with Potent Antitumor Activity
journal contribution
posted on 2020-03-12, 19:42 authored by Yang Wang, Xing Chen, Yaoyao Yan, Xiaochen Zhu, Mingming Liu, Xinhua LiuCyclin-dependent
kinases (CDKs) are promising therapeutic targets
for cancer therapy. Herein, we describe our efforts toward the discovery
of a series of 5-chloro-N4-phenyl-N2-(pyridin-2-yl)pyrimidine-2,4-diamine derivatives
as dual CDK6 and 9 inhibitors. Intensive structural modifications
lead to the identification of compound 66 as the most
active dual CDK6/9 inhibitor with balancing potency against these
two targets and good selectivity over CDK2. Further biological studies
revealed that compound 66 was directly bound to CDK6/9,
resulting in suppression of their downstream signaling pathway and
inhibition of cell proliferation by blocking cell cycle progression
and inducing cellular apoptosis. More importantly, compound 66 significantly inhibited tumor growth in a xenograft mouse
model with no obvious toxicity, indicating the promising therapeutic
potential of CDK6/9 dual inhibitors for cancer treatment. Therefore,
the above results are of great importance in the development of dual
CDK6/9 inhibitors for cancer therapy.