Synthetic Approaches and Clinical Application of Representative Small-Molecule Inhibitors of Cyclin-Dependent Kinase for Cancer Therapy

Abstract

The regulation of the cancer cell cycle heavily relies on cyclin-dependent kinases (CDKs). Targeting CDKs has been identified as a promising approach for effective cancer therapy. In recent years, there has been significant attention paid towards developing small-molecule CDK inhibitors in the field of drug discovery. Notably, five such inhibitors have already received regulatory approval for the treatment of different cancers, including breast tumors, lung malignancies, and hematological malignancies. This review provides an overview of the synthetic routes used to produce 17 representative small-molecule CDK inhibitors that have obtained regulatory approval or are currently being evaluated through clinical trials. It also discusses their clinical applications for treating CDK-related diseases and explores the challenges and limitations associated with their use in a clinical setting, which will stimulate the further development of novel CDK inhibitors. By integrating therapeutic applications, synthetic methodologies, and mechanisms of action observed in various clinical trials involving these CDK inhibitors, this review facilitates a comprehensive understanding of the versatile roles and therapeutic potential offered by interventions targeting CDKs.

Keywords: CDK; application; drugs; small molecule; synthesis.

Figure 1

The chemical structures of representative CDK inhibitors in the clinic.

Figure 2

Signaling pathway of CDK.

Scheme 1

Synthetic route of Palbociclib.

Scheme 2

Synthetic route of Ribociclib.

Scheme 3

Synthetic route of Abemaciclib.

Scheme 4

Synthetic route of Trilaciclib.

Scheme 5

Synthetic route of Dalpiciclib Isethionate.

Scheme 6

Synthetic route of Dinaciclib.

Scheme 7

Synthetic route of Ebvaciclib.

Scheme 8

Synthetic route of Monepantel.

Scheme 9

Synthetic route of TP-1287.

Scheme 10

Synthetic route of Enitociclib.

Scheme 11

Synthetic route of FIT-039.

Scheme 12

Synthetic route of Seliciclib.

Scheme 13

Synthetic route of Zotiraciclib.

Scheme 14

Synthetic route of BPI-16350.

Scheme 15

Synthetic route of Rigosertib Sodium.

Scheme 16

Synthetic route of Birociclib Succinate.

Scheme 17

Synthetic route of Lerociclib.