Design and Synthesis of Novel DFG-Out RAF/Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Inhibitors. 1. Exploration of [5,6]-Fused Bicyclic Scaffolds

Abstract

To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-b]pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, 1-6) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]thiazolo[5,4-b]pyridine derivative 6d showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of 6d (6d-SD) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (T/C = -7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that 6d is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity.

A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry

“…Some examples of BTA derivatives acting as agonists or antagonists of various receptors and enzymes are as follows- b-Arrestin-biased dopamine D2 receptor [287] 4 Vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors [288] 5 Apurinic/apyrimidinicendonuclease 1 inhibitors [289] 6…”

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

“…[48] Okaniwa and co-workersd eveloped derivatives of sorafenib (10)a sd ual inhibitors of BRAF(V600E) and VEGFR2 kinases for the treatment of varioush uman cancers. [49] The synthesis involved the hydrolysis of ethyl ester 57,f ollowed by Curtius rearrangement of the carboxylic acid in the presence of tert-butanol to give the Boc-protected amine. The Boc group was then deprotected to afford the 2-aminoimidazo[1,2-b]pyridazine derivative 58,w hich was then acylated to afford 59 (Scheme 15).…”

Exploring binding mechanisms of VEGFR2 with three drugs lenvatinib, sorafenib, and sunitinib by molecular dynamics simulation and free energy calculation

“…Okaniwa et al. () designed 27 inhibitors that have various [5,6] fused bicyclic scaffolds to target the DFG‐out state of VEGFR2 and found a promising inhibitor. Weimin et al.…”

“…Oguro et al (2010) identified one extremely potent compound targeting the DFG-out state of VEGFR2 by designing 30 novel pyrimidine derivatives. Okaniwa et al (2012) designed 27 inhibitors that have various [5,6] fused bicyclic scaffolds to target the DFG-out state of VEGFR2 and found a promising inhibitor. Weimin et al (2014) designed and synthesized a series of bis-aryl F I G U R E 1 (a) Structure of LEN-VEGFR2 in DFG-in state (PDB code: 3WZD), (b) structure of SOR-VEGFR2 in DFG-out state (PDB code: 3WZE); the G loop, the αC helix, and the A-loop were respectively shown in green-, purple-, and blue-colored cartoons, (c) chemical structures of the three drugs, LEN, SOR, and SUN [Colour figure can be viewed at wileyonlinelibrary.com] urea and bis-aryl amide derivates to bind to the DFG-out state of B-Raf V600E /VEGFR2, and one of them showed similarly equivalent antitumor efficacy in vivo, compared to Sorafenib.…”