Discovery of a potent and selective Axl inhibitor in preclinical model. (1st June 2021)

• Record Type: Journal Article
• Authors: Inoue, Satoshi; Yamane, Yoshinobu; Tsukamoto, Shuntaro; Azuma, Hiroshi; Nagao, Satoshi; Murai, Norio; Nishibata, Kyoko; Fukushima, Sayo; Ichikawa, Kenji; Nakagawa, Takayuki; Hata Sugi, Naoko; Ito, Daisuke; Kato, Yu; Goto, Aya; Kakiuchi, Dai; Ueno, Takashi; Matsui, Junji; Matsushima, Tomohiro
• Is Part Of: Bioorganic & medicinal chemistry. Volume 39(2021)
• Publication Date: 2021-06-01
• Subjects: Axl -- Mer -- Retinal toxicity -- Structure–activity relationships -- Cancer -- Inhibitor -- Small molecule; ALK anaplastic lymphorma kinase -- Boc tert-butoxycarbonyl -- Cbz benzyloxycarbonyl -- DCM dichloromethane -- DDR1 discoidin domain receptor 1 -- DMF N, N-dimethylformamide -- DMSO dimethyl sulfoxide -- EtOH ethanol -- Et3N triethylamine -- EtOAc ethyl acetate -- EtONa sodium ethoxide -- FLT3 fms-like tyrosine kinase 3 -- FLT4 fms-related tyrosine kinase 4 -- HATU 1-[Bis(dimethylamino)methylene]-1H-1, 2, 3-triazolo[4, 5-b]pyridinium 3-Oxide Hexafluorophosphate -- iPr2NEt N, N-Diisopropylethylamine -- K2CO3 potassium carbonate -- KDR kinase insert domain receptor -- MeOH methanol -- MgSO4 magnesium sulfate -- i-PrOH 2-propanol -- NaHCO3 sodium hydrogen carbonate -- NH4Cl ammonium chloride -- NMP N-methylpyrrolidone -- RT room temperature -- TAM Tyro3-Axl-Mer -- TBME tert-butyl methyl ether -- TFA trifluoroacetic acid -- THF tetrahydrofuran -- TLR toll-like receptor -- VEGFR2 vascular endothelial growth factor receptor 2; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2021.116137
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Axl and Mer are a members of the TAM (Tyro3-Axl-Mer) family of receptor tyrosine kinases, which, when activated, can promote tumor cell survival, proliferation, migration, invasion, angiogenesis, and tumor-host interactions. Chronic inhibition of Mer leads to retinal toxicity in mice. Therefore, successful development of an Axl targeting agent requires ensuring that it is safe for prolonged treatment. Here, to clarify whether enzyme inhibition of Mer by a small molecule leads to retinal toxicity in mice, we designed and synthesized Axl/Mer inhibitors and Axl-selective inhibitors. We identified an Axl/Mer dual inhibitor 28a, which showed retinal toxicity at a dose of 100 mg/kg in mice. Subsequent derivatization of a pyridine derivative led to the discovery of a pyrimidine derivative, 33g, which selectively inhibited the activity of Axl over Mer without retinal toxicity at a dose of 100 mg/kg in mice. Additionally, the compound displayed in vivo anti-tumor effects without influencing body weight in a Ba/F3-Axl isogenic subcutaneous model.