Targeting CDKs in cancer therapy: advances in PROTACs and molecular glues

Abstract

Essential transcription and cell cycle progression controllers are CDKs, whose dysregulation is a defining trait of many human cancers. CDKs have grown to be very crucial therapeutic targets in cancer. Although traditional CDK inhibitors have demonstrated therapeutic efficacy, they frequently encounter limitations due to resistance mechanisms and off-target effects. Recent developments in targeted protein degradation, like proteolysis-targeting chimeras (PROTACs) and molecular glues, offer creative ways to destroy CDK proteins specifically. These techniques reduce scaffolding activities and slow down kinase activity, hence more completely blocking oncogenic CDK signaling. This paper highlights the clinical and preclinical developments of PROTACs and molecular glues, investigates the current CDK-targeting therapeutic landscape, and studies the molecular basis of CDK dysregulation in cancer. We also address their benefits over conventional inhibitors, current issues, and possibilities for inclusion into precision oncology. These new approaches taken together represent a change in CDK-targeted cancer therapy.

Fig. 1. A defining quality of cancer is cell cycle dysregulation, which results in uncontrolled cell growth and tumor formation.

A signaling pathway network controlling DNA replication and mitosis methodically controls the cell cycle. In cancer, these regulatory networks are sometimes impaired, which leads to aberrant cell cycle progression and helps to cause cancer.

Fig. 2. The G1/S checkpoint, also known as the restriction, point in mammalian cells and the Start checkpoint in yeast, is a crucial regulatory mechanism that guarantees a cell is prepared to move from the G1 phase to the S phase of the cell cycle.

During this transition, the cell is committed to DNA replication and subsequent cell division.

Fig. 3. PROTAC Proteolytic Targeting Chimera.

The PROTAC (Proteolytic Targeting Chimera) mechanism is illustrated schematically. PROTAC is a bifunctional molecule that aids in the ubiquitin-proteasome system’s destruction of target proteins. A ternary complex is created when one ligand binds to an E3 ligase and the other ligand binds to the target protein. This connection facilitates the target protein’s ubiquitination and subsequent proteasomal destruction, providing a possible treatment approach for illnesses linked to abnormal protein accumulation or malfunction.