Discovery of Potent and Orally Bioavailable Diaminoquinazoline-Derived mRNA Decapping Scavenger (DcpS) Enzyme Inhibitors for Treatment of Solid Tumors
Spencer O. Scholz, Alexander S. Dudnik, Aristidis Vasilopoulos, Zhaozhong J. Jia, Anna Albertson, Brian S. Brown, Liye Chen, Renhe Li, Gaoyuan Ma, Longcheng Wang, Akinori Okano, Xianrui Zhao, Xingyu Jiang, Caleb Karmel, Patrick B. Brady, Chunqiu Lai, Hemantkumar Deokar, Felix DeAnda, Somdutta Roy, Manasi Mayekar, Hana Choi, Louis Lin, David G. Belair, Anand Joshi, Woo Hyun Yoon, Andrea Montano, Xiaoping Xie, Henry Nguyen, Haiyan S. Li, Chin Pan, Ben Danna, Deepak Gurbani, Jingzhi Li, Alla Korepanova, Tao Li, Tarikere Gururaja, Rong-Xian Ding, Rinku Jain, Ruth L. Martin, Rebecca Kohnken, Alexey RivkinAbstract
Decapping Scavenger (DcpS) enzyme, a pyrophosphatase involved in mRNA regulation via mRNA cap degradation, has been identified as a promising oncology target in fragile histidine triad (FHIT) deficient cancers such as AML and GBM but remains underexplored in broader solid tumor indications. We have discovered a novel DcpS inhibitor, compound 17, which has a differentiated binding mode relative to known inhibitors, engaging the second nucleotide-binding domain of the mRNA cap substrate. Compound 17 possesses superior levels of potency in NSCLC A549 cell line relative to known inhibitors and demonstrates excellent selectivity against DcpS-insensitive cell lines, high levels of bioavailability in preclinical species, and mitigated hERG liabilities. Finally, compound 17 demonstrates oral dose-dependent efficacy in two solid tumor xenograft models, A253 and EBC-1, highlighting the promise of DcpS as a novel target in FHIT low/deficient solid tumors.