One-pot two-step catalytic synthesis of 6-amino-2-pyridone-3,5-dicarbonitriles enabling anti-cancer bioactivity

We report a one-pot two-step synthesis of a bioactive 6-amino-2-pyridone-3,5-dicarbonitrile derivative using natural product catalysts betaine and guanidine carbonate. Anti-cancer bioactivity was observed in specific molecules within the library of 16 derivatives. Out of the compounds, 5o had the most potent anti-cancer activity against glioblastoma cells and was selected for further study. Compound 5o showed anti-cancer properties against liver, breast, lung cancers as well as primary patient-derived glioblastoma cell lines. Furthermore, 5o in combination with specific clinically relevant small molecule inhibitors induced enhanced cytotoxicity in glioblastoma cells. Through our current work, we establish a promising 6-amino-2-pyridone-3,5-dicarbonitrile based lead compound with anti-cancer activity either on its own or in combination with specific clinically relevant small molecule kinase and proteasome inhibitors

Synthesis of a Novel Pyrano[2,3-C]pyrazole Enabling PKBβ/AKT2 Inhibitory and in Vitro Anti-Glioma Activity

A series of novel pyrano[2,3-c]pyrazoles were synthesized and screened for their potential to inhibit kinases and exhibit anti-cancer activity against primary patient derived glioblastoma 2D cells and 3D neurospheres. A collection of 10 compounds were evaluated against glioma cell lines, with compound 4j exhibiting promising glioma growth inhibitory properties. Compound 4j was screened against 139 purified kinases and exhibited low micromolar activity against kinase AKT2/PKBβ. AKT signalling is one of the main oncogenic pathways in glioma and is often targeted for novel therapeutics. Indeed AKT2 levels correlated with glioma malignancy and poorer patient survival. Compound 4j inhibited the 3D neurosphere formation in primary patient derived glioma stem cells and exhibited potent EC50 against glioblastoma cell lines. Herein we establish a novel biochemical kinase inhibitory function for a pyrano[2,3-c]pyrazole derivative and further report its anti-glioma activity in vitro for the first time.</p

One-Pot Two-Step Catalytic Synthesis of Rationally Designed 6-amino-2-pyridone-3,5-dicarbonitriles Enabling Anti-Cancer Bioactivity

Herein we report a one-pot two-step synthesis of a bioactive 6-amino-2-pyridone-3,5-dicarbonitrile derivative using natural product catalysts betaine and guanidine carbonate. Upon identification of the anticancer bioactivity of the compound, we carried out structure-activity relationship and rationally designed a library of 16 derivatives. Out of the compounds, 5o had the most potent anti-cancer activity against murine glioblastoma cell lines and was selected for further study. Compound 5o showed anti-cancer properties against liver, breast, lung as well as primary patient-derived glioblastoma cell lines. Furthermore, 5o in combination with specific clinically relevant brain-penetrant small molecule inhibitors induces enhanced cytotoxicity in a murine glioblastoma cell line. Through our current work, we establish a promising 6-amino-2-pyridone-3,5-dicarbonitrile based lead compound with anti-cancer activity either on its own or in combination with specific clinically relevant small molecule kinase and proteasome inhibitors

Dual inhibition of HSF1 and DYRK2 impedes cancer progression

Preserving proteostasis is a major survival mechanism for cancer. DYRK2 is a key oncogenic kinase that directly activates the transcription factor HSF1 and the 26S proteasome. Targeting DYRK2 has proven to be a tractable strategy to target cancers sensitive to proteotoxic stress, however, the development of HSF1 inhibitors remains in its infancy. Importantly, multiple other kinases have been shown to redundantly activate HSF1 which promoted ideas to directly target HSF1. The eventual development of direct HSF1 inhibitor KRIBB11 suggests that the transcription factor is indeed a druggable target. The current study establishes that concurrent targeting of HSF1 and DYRK2 can indeed impede cancer by inducing apoptosis faster than individual targetting. Furthermore, targeting the DYRK2-HSF1 axis induces death in proteasome inhibitor resistant cells and reduces triple-negative breast cancer burden in ectopic and orthotopic xenograft models. Together the data indicate that co-targeting of kinase DYRK2 and its substrate HSF1 could prove to be a beneficial strategy in perturbing neoplastic malignancies