Zhe Guan

Background and Objective: CDK7, a member of the CDK-activating kinase (CAK) family, plays a key role in cell cycle, transcriptional regulation and in regulating the proliferation and apoptosis of tumor cells. Some evidence suggests that CDK7 is a promising target for cancer treatments, so it is of great significance to develop an efficient and highly selective CDK7 inhibitor. CDK7 inhibitors have not yet been marketed. This review focuses on some selective CDK7 inhibitors currently in clinical research, and introduces their targets, indications, and the latest clinical trial progress in detail. Methods: We investigated the recent advances in development of CDK7 inhibitors and their clinical trials from online website (Google Scholar, ClinicalTrials.gov) and electronic databases [PubMed, CDDI (Cortellis Drug Discovery Intelligence)]. Key Content and Findings: CDK7, as an important pathway key node, is involved in the regulation and transcription of the cell cycle, and is highly expressed in a variety of tumor cells, which is a good biomarker. In addition, CDK7 plays a key role in regulating the proliferation and apoptosis of tumor cells. By selectively inhibiting CDK7 activity in tumor tissues, it can play a positive role in tumor treatment. Compared with the first-generation pan-CDK7 inhibitors, the second-generation selective CDK7 inhibitors have more potent activity, better selectivity and druggability. Selective CDK7 inhibitors currently under investigation are mainly divided into two categories: (I) selective covalent CDK7 inhibitors and (II) selective non-covalent CDK7 inhibitors. This review summarizes the recent findings on selective CDK7 inhibitors, with a focus on their indications, and the latest clinical trial progress. Conclusions: Overall, CDK7 is a very promising anti-tumor target for the treatment of breast cancer, solid tumors, ovarian cancer and triple negative breast cancer (TNBC), etc. There is no doubt about that, however, its specific inhibitors still need to be developed with scientists’ tireless efforts.

Concomitant inhibition of MAPK and PI3K signaling pathways has been recognized as a promising strategy for cancer therapy, which effectively overcomes the drug resistance of MAPK signaling pathway-related inhibitors. Herein, we report the scaffold-hopping generation of a series of 1H-pyrazolo[3,4-d]pyrimidine dual ERK/PI3K inhibitors. Compound 32d was the most promising candidate, with potent inhibitory activities against both ERK2 and PI3Kα which displays superior anti-proliferative profiles against HCT116 and HEC1B cancer cells. Meanwhile, compound 32d possessed acceptable pharmacokinetic profiles and showed more efficacious anti-tumor activity than GDDC-0980 and the corresponding drug combination (BVD-523 + GDDC-0980) in HCT-116 xenograft model, with a tumor growth inhibitory rate of 51% without causing observable toxic effects. All the results indicated that 32d was a highly effective anticancer compound and provided a promising basis for further optimization towards dual ERK/PI3K inhibitors.

Transition-metal-catalyzed tandem Heck/carbonylation reaction has emerged as a powerful tool for the synthesis of structurally diverse carbonyl molecules, as well as natural products and pharmaceuticals. However, the asymmetric version was rarely reported, and remains a challenging topic. Herein, we describe a palladium-catalyzed asymmetric tandem Heck/carbonylation desymmetrization of cyclopentenes. Alcohols, phenols and amines are employed as versatile coupling reagents for the construction of multifunctional chiral bicyclo[3.2.1]octanes with one all-carbon quaternary and two tertiary carbon stereogenic centers in high diastereo- and enantioselectivities. This study represents an important progress in both the asymmetric tandem Heck/carbonylation reactions and enantioselective difunctionalization of internal alkenes.