Pyrazoloadenine Inhibitors of the RET Lung Cancer Oncoprotein Discovered via a Fragment Optimization Approach.

Pyrazoloadenine Inhibitors of the RET Lung Cancer Oncoprotein Discovered via a Fragment Optimization Approach. ChemMedChem. 2021 Feb 08;: Authors: Frett B, Saha D, Ryan KR, Lakkaniga NR, Smith EL Abstract A fragment-based drug discovery approach using a pyrazoloadenine fragment library was utilized to uncover new molecules that target the RET (REarranged during Transfection) oncoprotein, which is a driver oncoprotein in ~2% of non-small cell lung cancer. The fragment library was screened against the RET kinase and LC-2/ad (RET-driven), KM-12 (TRKA driven- matched control) and A549 (cytotoxic control) cells to identify selective scaffolds that could inhibit RET-driven growth. An unsubstituted pyrazoloadenine fragment was found active on RET in a biochemical assay but reduced cell viability in non-RET driven cell lines (EC50 = 1 µM and 3 µM, respectively). To increase selectivity for RET, the pyrazoloadenine was modeled in the RET active site, and two domains were identified that were probed with pyrazoloadenine fragment derivatives to improve RET affinity. Scaffolds at each domain were merged to generate a novel lead compound, 8p, which exhibited improved activity and selectivity for the RET oncoprotein (A549 EC50 = 5.92 µM, LC-2/ad EC50 = 0.016 µM, RET IC50 = 0.000326 µM). PMID: 33559353 [PubMed - as supplied by publisher]
Source: ChemMedChem - Category: Chemistry Authors: Tags: ChemMedChem Source Type: research