THZ531 and Neoplasms

Cyclin-dependent kinase (CDK) 7 has a unique functional repertoire by virtue of its dual role in transcription and cell cycle progression. Whereas CDK7 is ubiquitously expressed in various types of cancer, its downregulation leads to reduced cell proliferation. Importantly, it is now agreed that targeting transcription selectively limits the synthesis of mRNAs involved in tumor growth without causing an outage of transcription of housekeeping genes. Thus, CDK7 has been considered as a viable therapeutic target in cancer. Indeed, the development of CDK7 inhibitors has gained huge momentum with two molecules, CT7001 and SY-1365, currently under clinical development. Herein, we discuss the latest understanding of the role of CDK7 in cancer cells and provide an overview of the pharmacophores of CDK7 inhibitors, their efficacy in various cancer models, and their clinical development.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase-Activating Kinase; Cyclin-Dependent Kinases; Humans; Neoplasms; Protein Kinase Inhibitors

Personalized medicine and therapies represent the goal of modern medicine, as drug discovery strives to move away from one-cure-for-all and makes use of the various targets and biomarkers within differing disease areas. This approach, especially in oncology, is often undermined when the cells make use of alternative survival pathways. As such, acquired resistance is unfortunately common. In order to combat this phenomenon, synthetic lethality is being investigated, making use of existing genetic fragilities within the cancer cell. This Perspective highlights exciting targets within synthetic lethality, (PARP, ATR, ATM, DNA-PKcs, WEE1, CDK12, RAD51, RAD52, and PD-1) and discusses the medicinal chemistry programs being used to interrogate them, the challenges these programs face, and what the future holds for this promising field.

Topics: Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; Cyclin-Dependent Kinases; DNA-Activated Protein Kinase; Genes, BRCA2; Humans; Neoplasms; Poly(ADP-ribose) Polymerases; Precision Medicine; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Rad51 Recombinase; Synthetic Lethal Mutations