NOVEL SMALL MOLECULE KINASE INHIBITORS AS TUMOR-AGNOSTIC THERAPEUTICS

This study has focused on the role of novel boronic acid (BA) and nicotinamide-ponatinib analogs to address current limitations in the treatment of difficult-to-treat cancers including renal, breast and lung cancer. As is well-known, CLK and ROCK have been implicated as oncogenic kinases across several cancer types. However, there are research gaps in the development of CLK/ROCKi. For instance, currently none of the CLKi have been FDA-approved. This study has identified novel BA-containing pyrazolo[4,3-f]quinoline scaffolds that are potent, dual CLK/ROCKi, which are highly active against the renal cancer cell line, Caki-1 based on the NCI screening data. Based on kinase and cancer cell line screening, the top compounds were identified and mechanistic studies indicated that the compounds promoted DNA damage in Caki-1. We also gained insight into the binding modes of the compounds via docking analysis. Furthermore, flow cytometry analysis indicated that the top compounds promote cell cycle arrest. Additionally, qPCR and western analysis indicated that the top compound, HSD1791, suppresses cyclinD/Rb pathway, thereby providing a mechanistic basis for cell cycle arrest. Concerning the challenges in the treatment of breast and lung cancer, it is known that despite advances in chemotherapy and immunotherapy, the survival rate of patients is poor at the advanced stage of the diseases. Oncogenic kinases such as p70S6K and MNK have been independently implicated in breast and lung tumorigenesis, however synergistically targeting MNK/p70S6K pathways using single agents remains a challenge. In this study, we have identified the novel lead candidate, HSND80, which is a potent dual MNK/p70S6Ki with remarkable activity against breast and non-small cell lung cancer cell lines. We identified the mechanism of tumor cell growth suppression using proteomics, immunoblotting, and cell cycle analysis. Moreover, HSND80 has demonstrated tumor growth suppression effects in vivo. Additionally, pharmacokinetics, plasma protein binding, and hERG safety analysis indicated HSND80 has suitable drug-like properties. Together, these findings indicate that it has promising functions as an anticancer therapeutic. In conclusion, this study has focused on identifying and characterizing novel pyrazolo[4,3-f]quinoline scaffolds and nicotinamide ponatinib analogs as promising tumor-agnostic therapeutics.