Development of a Potent Brain-Penetrant EGFR Tyrosine Kinase Inhibitor against Malignant Brain Tumors

Abstract

The epidermal growth factor receptor (EGFR) is genetically altered in nearly 60% of glioblastoma tumors; however, tyrosine kinase inhibitors (TKIs) against EGFR have failed to show efficacy for patients with these lethal brain tumors. This failure is attributed to the inability of clinically tested EGFR TKIs to cross the blood–brain barrier (BBB) and achieve adequate pharmacological levels to inhibit various oncogenic forms of EGFR that drive glioblastoma. Through SAR analysis, we developed compound 5 (JCN037) from an anilinoquinazoline scaffold by ring fusion of the 6,7-dialkoxy groups to reduce the number of rotatable bonds and polar surface area and by introduction of an ortho-fluorine and meta-bromine on the aniline ring for improved potency and BBB penetration. Relative to the conventional EGFR TKIs erlotinib and lapatinib, JCN037 displayed potent activity against EGFR amplified/mutant patient-derived cell cultures, significant BBB penetration (2:1 brain-to-plasma ratio), and superior efficacy in an EGFR-driven orthotopic glioblastoma xenograft model.

Intramolecular N−H⋅⋅⋅F Hydrogen Bonding Interaction in a Series of 4‐Anilino‐5‐Fluoroquinazolines: Experimental and Theoretical Characterization of Electronic and Conformational Effects

“…The synthesis and X-ray crystal structure data of compound 4 (JCN037) is reported in ref. [18]. The synthesis of compounds 5-31, S1, and S2 is described in the Supporting Information, which also provides characterization of the compounds, crystallographic data, NMR spectra, and computational details.…”

“…During one of our recent medicinal chemistry programs on brain-penetrant EGFR tyrosine kinase inhibitors, [18] we tried to improve the metabolic stability of our lead compound 4 (JCN037) through introduction of a fluorine atom at position 5 of the quinazoline scaffold to obtain fluorinated analogue 5. We were surprised to observe a pronounced downfield shift of the NH signal by 1.18 ppm in the 1 H NMR spectrum, and a strong splitting into a doublet with 1h J NH,F = 19.6 Hz (Figure 2 and Table 1).…”

“…Quite serendipitously, during one of our medicinal chemistry research programs on 4-anilinoquinazolines, [18] we noticed a remarkably strong through-space nuclear spin-spin coupling ( 1h J NH,F ) for a fluorinated anilinoquinazoline analogue. Based on this observation, we set out to prepare a series of related 4-anilino-6,7-ethylenedioxy-5-fluoroquinazolines, that we report in the present study for the characterization of the (aniline) NH•••F interaction (Figure 1C).…”

Presenting a Special Issue on “Medicinal Chemistry: From Targets to Therapies”

“…Viewpoints provide perspectives on isosteric replacements of anilines (Sodano et al) and deuterium-switches (DeWitt et al) . Innovations demonstrate the utility of phenotypic drug discovery strategies (Childers et al), allosteric modulators (Han et al), and brain-penetrant EGFR tyrosine kinase inhibitors (Tsang et al) . The Patent Highlights discuss the development of dual specificity tyrosine phosphorylation regulated kinase-1 A (DYRK1A) inhibitors (Kargbo), a SMARCA2/4 PROTAC (Kargbo), and C-RAF and EGFR combination therapy (Kargbo) …”

“…36 Innovations demonstrate the utility of phenotypic drug discovery strategies (Childers et al), 37 allosteric modulators (Han et al), 38 and brain-penetrant EGFR tyrosine kinase inhibitors (Tsang et al). 39 The Patent Highlights discuss the development of dual specificity tyrosine phosphorylation regulated kinase-1 A (DYRK1A) inhibitors (Kargbo), 40 a SMARCA2/4 PROTAC (Kargbo), 41 and C-RAF and EGFR combination therapy (Kargbo). 42 Our 10-year anniversary issue includes contributions from authors in Australia, China, Denmark, Germany, Italy, Japan, Poland, Singapore, Taiwan, and the USA, reflecting the truly international nature of contemporary Science.…”