CNX-1351 / BMS - LARVOL DELTA

Single-cycle Rift Valley fever virus particles from stable replicon cells enable discovery of antiviral CNX-1351 for multiple RNA viruses. (PubMed, Virol Sin) - "Mechanistic studies revealed that CNX-1351 inhibits viral replication, potentially by targeting the PI3K-Akt signaling pathway. This single-cycle VRP system provides a valuable tool for studying RVFV biology, host interactions, antiviral and vaccine development under reduced biosafety constraints."

Journal • Respiratory Diseases

Covalent Proximity Scanning of a Distal Cysteine to Target PI3Kα. (PubMed, J Am Chem Soc) - "In rat liver microsomes, compounds 19 and 22 outperformed the rapidly metabolized CNX-1351, the only known PI3Kα irreversible inhibitor...In SKOV3 cells, compounds 19 and 22 revealed PI3Kβ-dependent signaling, which was sensitive to TGX221. Compounds 19 and 22 thus qualify as specific chemical probes to explore PI3Kα-selective signaling branches. The proposed approach is generally suited to develop covalent tools targeting distal, unexplored Cys residues in biologically active enzymes."

Journal • Oncology • PIK3CA • PIK3CB

[VIRTUAL] Volume scanning, a rational approach to covalent PI3Kα inhibitors (AACR 2021) - "Inhibitors of the phosphatidylinositol 3-kinase (PI3K) - protein kinase B (PKB/Akt) - mechanistic target of rapamycin (mTOR) axis are considered valuable assets in cancer therapy. A considerable effort has been dedicated to the development of drugs targeting class I PI3Ks, which are evaluated in preclinical and clinical studies.[1-5] Here we present a strategy to convert a phase II clinical candidate, a pan-PI3K inhibitor (PQR309, bimiralisib)[5,6], into a highly selective, covalent PI3Kα inhibitor with the aim to minimize off-target and on-target metabolic side effects of PI3K inhibitor cancer therapy...Our pilot compounds exceed specificity and potency over an experimental dimethyl-substituted enone, CNX-1351.[7] Moreover, our compounds display increased stability in rat liver microsomal assays and outperform the rapidly metabolized CNX-1351...Moreover, we provide highly selective chemical tools to dissect PI3K isoform signaling in physiology and disease. A..."

Oncology • mTOR

[VIRTUAL] Development of optimized chemical probes targeting PI3Ka to deconvolute the role of class I PI3Ks isoforms in insulin signaling (AACR 2021) - "However, the availability of claimed isoform-selective PI3Kα inhibitors is limited to BYL719 (Alpelisib)[6] and GDC0032 (Taselisib)[7], which do not maintain PI3Kα selectivity at a concentration required in cellular experimental settings and clinical applications...An extensive Structure Activity Relationship (SAR) study was performed using CNX-1351[8] reacting group and introducing different heteroaliphatic rings in the linker...The generation of a novel class of covalent PI3Kα-specific inhibitors with improved selectivity and persistency of PI3Kα-inhibition will shed light on the role of PI3Kα in cancer and metabolism. Our results will pave the way for the dissociation of PI3Ki antitumor activity from adverse effects on insulin action."

Oncology

[VIRTUAL] A novel, highly potent PI3Kα covalent inhibitor deconvolutes class I PI3K isoforms in cancer cells (AACR 2021) - "Overall, 19 exhibited excellent cellular activity with a superior profile compared to CNX-1351[3], a previously reported covalent PI3Kα inhibitor...Importantly, 19 provided a considerable gain in potency over BYL719, a clinically approved non-covalent PI3Kα-selective inhibitor...This strategy is a step towards the development of drug-like, isoform-selective, covalent PI3K inhibitor scaffolds, and 19 provides a template for the development of PI3Kα inhibitors with overall reduced adverse side effects in cancer therapy. Moreover, our covalent inhibition strategy will pave the way for a better molecular understanding of PI3K isoform signaling in general."

Oncology • FOXO1 • PTEN