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Pyrazoloadenine Inhibitors of the RET Lung Cancer Oncoprotein Discovered by a Fragment Optimization Approach
Author(s) -
Saha Debasmita,
Ryan Katie Rose,
Lakkaniga Naga Rajiv,
Smith Erica Lane,
Frett Brendan
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100013
Subject(s) - fragment (logic) , chemistry , a549 cell , transfection , protein kinase domain , kinase , cancer research , drug discovery , cell culture , small molecule , microbiology and biotechnology , cell , biology , biochemistry , gene , genetics , computer science , mutant , programming language
A fragment‐based drug‐discovery approach was used on a pyrazoloadenine fragment library to uncover new molecules that target the RET (REarranged during Transfection) oncoprotein, which is a driver oncoprotein in ∼2 % of non‐small‐cell lung cancers. 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 to be active on RET in a biochemical assay, but reduced cell viability in non‐RET‐driven cell lines (EC 50 =1 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, 8 p , which exhibited improved activity and selectivity for the RET oncoprotein (A549 EC 50 =5.92 μM, LC‐2/ad EC 50 =0.016 μM, RET IC 50 =0.000326 μM).