THZ531 and Breast-Neoplasms

Sustained proliferative capacity and gene dysregulation are hallmarks of cancer. In mammalian cells, cyclin-dependent kinases (CDKs) control critical cell cycle checkpoints and key transcriptional events in response to extracellular and intracellular signals leading to proliferation. Significant clinical activity for the treatment of hormone receptor positive metastatic breast cancer has been demonstrated by palbociclib, ribociclib and abemaciclib, dual CDK4/6 inhibitors recently FDA-approved. SY-1365, a CDK7 inhibitor has shown initial encouraging data in phase I for solid tumors treatment. These results have rejuvenated the CDKs research field. This review provides an overview of relevant advances on CDK inhibitor research since 2015 to 2019, with special emphasis on transcriptional CDK inhibitors, new emerging strategies such as target protein degradation and compounds under clinical evaluation.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Benzimidazoles; Breast Neoplasms; Cell Cycle Checkpoints; Cyclin-Dependent Kinases; Drug Discovery; Humans; Indoles; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Pyrimidines; Transcription Factors

Deep learning-based in silico alternatives have been demonstrated to be of significant importance in the acceleration of the drug discovery process and enhancement of success rates. Cyclin-dependent kinase 12 (CDK12) is a transcription-related cyclin-dependent kinase that may act as a biomarker and therapeutic target for cancers. However, currently, there is no high selective CDK12 inhibitor in clinical development and the identification of new specific CDK12 inhibitors has become increasingly challenging due to their similarity with CDK13. In this study, we developed a virtual screening workflow that combines deep learning with virtual screening tools and can be applied rapidly to millions of molecules. We designed a Transformer architecture Drug-Target Interaction (DTI) model with dual-branched self-supervised pre-trained molecular graph models and protein sequence models. Our predictive model produced satisfactory predictions for various targets, including CDK12, with several novel hits. We screened a large compound library consisting of 4.5 million drug-like molecules and recommended a list of potential CDK12 inhibitors for further experimental testing. In kinase assay, compared to the positive CDK12 inhibitor THZ531, the compounds CICAMPA-01, 02, 03 displayed more effective inhibition of CDK12, up to three times as much as THZ531. The compounds CICAMPA-03, 05, 04, 07 showed less inhibition of CDK13 compare to THZ531. In vitro, the IC50 of CICAMPA-01, 04, 05, 06, 09 was less than 3 μM in the HER2 positive CDK12 amplification breast cancer cell line BT-474. Overall, this study provides a highly efficient and end-to-end deep learning protocol, in conjunction with molecular docking, for discovering CDK12 inhibitors in cancers. Additionally, we disclose five novel CDK12 inhibitors. These results may accelerate the discovery of novel chemical-class drugs for cancer treatment.

Topics: Breast Neoplasms; Cyclin-Dependent Kinases; Deep Learning; Female; Humans; Molecular Docking Simulation

Cyclin-dependent kinase 12 (CDK12) plays a key role in the coordination of transcription with elongation and mRNA processing. CDK12 mutations found in tumors and CDK12 inhibition sensitize cancer cells to DNA-damaging reagents and DNA-repair inhibitors. This suggests that CDK12 inhibitors are potential therapeutics for cancer that may cause synthetic lethality. Here, we report the discovery of 3-benzyl-1-( trans-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea derivatives as novel and selective CDK12 inhibitors. Structure-activity relationship studies of a HTS hit, structure-based drug design, and conformation-oriented design using the Cambridge Structural Database afforded the optimized compound 2, which exhibited not only potent CDK12 (and CDK13) inhibitory activity and excellent selectivity but also good physicochemical properties. Furthermore, 2 inhibited the phosphorylation of Ser2 in the C-terminal domain of RNA polymerase II and induced growth inhibition in SK-BR-3 cells. Therefore, 2 represents an excellent chemical probe for functional studies of CDK12 and could be a promising lead compound for drug discovery.

Topics: Breast Neoplasms; Cell Survival; Cyclin-Dependent Kinases; Drug Discovery; Enzyme Inhibitors; Female; Humans; Phosphorylation; RNA Polymerase II; Structure-Activity Relationship; Tumor Cells, Cultured