Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Focused chemical libraries based on a plethora of scaffolds have resulted in mixed success with regard to the development of selective CDK9 inhibitors. Here we review the regulation of CDK9, its cellular functions, and common core structures used to target CDK9, along with their selectivity profile and efficacy in vitro and in vivo.

Despite the fact that many small molecule inhibitors have been approved for cancer therapy, we still have a mighty long road to traverse in the field of targeted therapy against cancer. In order to overcome the challenges of chemo resistance and selectivity, we designed and synthesized 1,2,3-triazole appended indole-chalcone derivatives (4 a-q) and evaluated their antioxidant, anticancer and DNA binding properties. Among all the analogs, compounds with o-chloro (4b), o-fluoro (4h) and p-fluoro (4j) substitution exhibited potent antioxidant activity and the potency of 4 b was comparable to the standard ascorbic acid. In a cell based screen, compound 4 b inhibited the growth of human cervical cancer (SiHa) and colorectal epithelial carcinoma (SW620) cancer cell lines with an IC 50 values of 67.99 and 48.96 mg mL À1 , respectively without showing any significant cytotoxicity in human embryonic kidney cells (HEK293) at the similar concentration. To gain insight into the DNA-binding ability, various spectroscopic techniques such as UV-visible, fluorescence, circular dichroism, viscosity and cyclic voltametric studies were performed. These studies exposed that compounds 4 b, 4 h and 4 j act via noncovalent intercalative mode of binding to DNA causing their antiproliferative activity, supported by molecular docking studies. Our study revealed the non-toxic nature and potent activity of compound 4 b makes it a suitable candidate for further optimization and pharmacological studies.

Although CAR T cell therapies have proven to be effective in treating hematopoietic cancers, their abilities to regress solid tumors have been less encouraging. Mechanisms to explain these disparities have focused primarily on differences in cancer cell heterogeneity, barriers to CAR T cell penetration of solid tumors, and immunosuppressive microenvironments. To evaluate the contributions of immunosuppressive tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) on CAR T cell efficacies, we have exploited the ability of a folate-targeted Toll-like receptor 7 agonist (FA-TLR7-1A) to specifically reactivate TAMs and MDSCs from an immunosuppressive to pro-inflammatory phenotype without altering the properties of other immune cells. We report here that FA-TLR7-1A significantly augments standard CAR T cell therapies of 4T1 solid tumors in immune competent mice. We further show that co-administration of the FA-TLR7-1A with the CAR T cell therapy not only repolarizes TAMs and MDSCs from an M2-like anti-inflammatory to M1-like pro-inflammatory phenotype, but also enhances both CAR T cell and endogenous T cell accumulation in solid tumors while concurrently increasing their states of activation. Because analogous myeloid cells in healthy tissues ar not altered by administration of FA-TLR7-1A, no systemic activation of the immune system nor accompanying weight loss is observed. These data argue that immunosuppressive myeloid cells contribute prominently to the failure of CAR T cells to eradicate solid tumors and suggest that methods to reprogram tumor associated myeloid cells to a more inflammatory phenotype could significantly augment the potencies of CAR T cell therapies.

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Inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) is a key regulator of the cannonical NF-κB pathway. IKKβ has been validated as a drug target for pathological conditions, which...