Selective inhibition of CDK4/6: A safe and effective strategy for developing anticancer drugs.
10.1016/j.apsb.2020.05.001
- Author:
Kai YUAN
1
;
Xiao WANG
1
;
Haojie DONG
1
;
Wenjian MIN
1
;
Haiping HAO
1
;
Peng YANG
1
Author Information
1. State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
- Publication Type:Review
- Keywords:
AKT, protein kinase B;
AML, acute myeloid leukemia;
CDK4/6;
CDKs, cyclin-dependent kinases;
CIP/KIP, cyclin-dependent kinase inhibitor 1/kinase inhibitory protein;
CKIs, cyclin-dependent kinase inhibitors;
CPU, China Pharmaceutical University;
CRPC, castration-resistant prostate cancer;
Cancer;
Cell cycle;
Drug resistance;
ER, estrogen receptor;
ERK, extracellular regulated protein kinases;
FDA, U.S. Food and Drug Administration;
FLT, fms-like tyrosine kinase;
HER2, human epidermal growth factor receptor 2;
INK4, inhibitors of CDK4;
JAK, janus kinase;
MCL, mantle cell lymphoma;
MM, multiple myeloma;
NSCLC, non-small cell lung cancer;
ORR, overall response rates;
PDK1, 3-phosphoinositide-dependent protein kinase 1;
PFS, progression-free survival;
PI3K, phosphatidylinositol 3-hydroxy kinase;
PR, progesterone receptor;
PROTAC;
PROTAC, proteolysis targeting chimera;
RB, retinoblastoma protein;
SPH, Shanghai Pharmaceuticals Holding Co., Ltd.;
STATs, signal transducers and activators of transcription;
Selectivity;
UNISA, University of South Australia
- From:
Acta Pharmaceutica Sinica B
2021;11(1):30-54
- CountryChina
- Language:English
-
Abstract:
The sustained cell proliferation resulting from dysregulation of the cell cycle and activation of cyclin-dependent kinases (CDKs) is a hallmark of cancer. The inhibition of CDKs is a highly promising and attractive strategy for the development of anticancer drugs. In particular, third-generation CDK inhibitors can selectively inhibit CDK4/6 and regulate the cell cycle by suppressing the G1 to S phase transition, exhibiting a perfect balance between anticancer efficacy and general toxicity. To date, three selective CDK4/6 inhibitors have received approval from the U.S. Food and Drug Administration (FDA), and 15 CDK4/6 inhibitors are in clinical trials for the treatment of cancers. In this perspective, we discuss the crucial roles of CDK4/6 in regulating the cell cycle and cancer cells, analyze the rationale for selectively inhibiting CDK4/6 for cancer treatment, review the latest advances in highly selective CDK4/6 inhibitors with different chemical scaffolds, explain the mechanisms associated with CDK4/6 inhibitor resistance and describe solutions to overcome this issue, and briefly introduce proteolysis targeting chimera (PROTAC), a new and revolutionary technique used to degrade CDK4/6.
