Thursday, January 14, 2021

Targeting EGFR in glioblastoma with a novel brain-penetrant small molecule EGFR-TKI

Jing Ni, Yanzhi Yang, Qiwei Wang, Johann S. Bergholz, Tao Jiang, Thomas M. Roberts, Nathanael S. Gray, Jean J. Zhao


Epidermal growth factor receptor (EGFR) is mutated or amplified in a majority of glioblastoma (GBM), and its mutation and focal amplification correlate with a more aggressive disease course. However, EGFR-directed tyrosine kinase inhibitors (TKIs) tested to date have yielded minimal clinical benefit. Here, we report a novel covalent EGFR-TKI, CM93, as a potential specific drug to target adult GBMs with aberrant EGFR. CM93 has extraordinary brain-selective distribution, with a brain-to-plasma ratio greater than 20 (>2,000% brain penetration). While all currently approved EGFR-TKIs are subject to extensive efflux transporter activity, CM93 is not a substrate of efflux transporters (P-gp and BCRP). Pre-clinical efficacy studies showed that CM93 is more effective than other EGFR-TKIs in blocking the proliferation of GBM tumor cells from both patient-derived and cultured human GBM cell lines with EGFR amplification and/or EGFRvIII mutation. In addition, CM93 administered as a single agent was able to attenuate the growth of orthotopic U251-EGFRvIII xenografts and extend the survival of tumor-bearing mice in a dose-dependent manner. Moreover, CM93 inhibited EGFR phosphorylation in GBM tumors derived from a novel genetically-engineered mouse (GEM) model of GBM with EGFRvIII expression both in vitro and in vivo. CM93 also extended the survival of mice bearing orthotopic allografts of GBM. Notably, mice maintained stable body weight during treatments with increasing doses of CM93 up to 75 mg/kg per day. Together, these data suggest that CM93 is a potential EGFR-TKI well suited for the treatment of adult GBM with mutant EGFR.

Covalent drug discovery using sulfur(VI) fluoride exchange warheads

Huang Huang, Lyn H. Jones Expert Opinion on Drug Discovery , 2023 Covalent drug discovery has ...