CDK2

Introduction:The success of the CDK4/6 inhibitor Ibrance™ (Palbociclib) as an anticancer agent inspired and directed more efforts toward the discovery of selective cyclin-dependent kinase (CDKs) inhibitors. CDK2 is a member of the CDKs family that plays an important role in regulating the progression of cells into both S- and M-phases of the cell cycle. Studies suggest that overexpression of CDK2 may be implicated in tumor growth in cancer.Areas covered:This review covers the patent literature of CDK2 inhibitors published between 2017 and 2021. We searched the online databases of the European Patent Office, American Chemical Society, and Google patents.Expert opinion:Developing selective CDK2 inhibitors is challenging due to the absence of a previously approved selective CDK2 inhibitor. However, ongoing efforts by Incyte Corporation and Pfizer Inc., which are reported herein, may stand out as a new starting point and bring novel information critical for the medicinal chemistry and drug design scientists in the field of CDK2 inhibitors' development.

A distinct hallmark of acute myeloid leukemia (AML) is the arrest of leukemic myeloblasts at an immature stage of development. Therapies that overcome differentiation arrest have emerged as a powerful strategy for treating AML, but targeting leukemia differentiation remains challenging, mainly because of an incomplete mechanistic understanding of the process. Here, we unveil a new role for cyclin-dependent kinase 2 (CDK2) in blocking myeloid differentiation in AML. We show that among several interphase CDK, only CDK2 undergoes ubiquitin-dependent proteasome degradation, which is accompanied by AML cell differentiation. By using the yeast 2-hybrid system and functional analyses, KLHL6 was identified as a specific E3 ubiquitin ligase regulating the degradation of CDK2. Importantly, inhibiting CDK2, but not other cyclin-dependent kinases CDK1/4/6, effectively induced granulocytic differentiation in AML cell lines and 5 major subtypes of primary patient-derived AML samples. Mechanistically, CDK2 depletion led to the reactivation of differentiation pathway translation, and the differentiation blockade function of CDK2 may be achieved directly by maintaining the activity of PRDX2. Finally, CDK2 depletion arrested tumor growth of AML cells in nude mice and extended survival in both AML cell line and PDX-AML cells derived xenograft mouse models. Thus, our work not only provides experimental evidence for validating CDK2 as a potential therapeutic target for differentiation, but also uncovers the biological function of the CDK2-PRDX2 axis in blocking AML differentiation.

DNA replication must be precisely controlled in order to maintain genome stability. Transition through cell cycle phases is regulated by a family of Cyclin-Dependent Kinases (CDKs) in association with respective cyclin regulatory subunits. In normal cell cycles, E-type cyclins (Cyclin E1 and Cyclin E2,CCNE1andCCNE2genes) associate with CDK2 to promote G1/S transition. Cyclin E/CDK2 complex mostly controls cell cycle progression and DNA replication through phosphorylation of specific substrates. Oncogenic activation of Cyclin E/CDK2 complex impairs normal DNA replication, causing replication stress and DNA damage. As a consequence, Cyclin E/CDK2-induced replication stress leads to genomic instability and contributes to human carcinogenesis. In this review, we focus on the main functions of Cyclin E/CDK2 complex in normal DNA replication and the molecular mechanisms by which oncogenic activation of Cyclin E/CDK2 causes replication stress and genomic instability in human cancer.