Discovery of ^wtRET and ^V804MRET Inhibitors: From Hit to Lead

Abstract

Oncogenic activation of RET kinase has been found in several neoplastic diseases, like medullary thyroid carcinoma, multiple endocrine neoplasia, papillary thyroid carcinoma, and non‐small‐cell lung cancer. Currently approved RET inhibitors were not originally designed to be RET inhibitors, and their potency against RET kinase has not been optimized. Hence, novel compounds able to inhibit both wild‐type RET (wtRET) and its mutants (e.g., V804MRET) are needed. Herein we present the development and the preliminary evaluation of a new sub‐micromolar wtRET/V804MRET inhibitor, N‐(2‐fluoro‐5‐trifluoromethylphenyl)‐N′‐{4′‐[(2′′‐benzamido)pyridin‐4′′‐ylamino]phenyl}urea (69), endowed with a 4‐anilinopyridine structure, starting from our previously identified 4‐anilinopyrimidine hit compound. Profiling against a panel of kinases indicated 69 as a multi cKIT/wtRET/V804MRET inhibitor.

Novel targeted therapeutics for MEN2

“…Several small molecules have been designed, developed or repurposed as RET kinase inhibitors during the past decade (reviewed in Phay & Shah 2010, Mologni 2011, Borrello et al 2013, Mologni et al 2017a. Some have already been approved for non-MEN2 thyroid cancer and are under investigation for MEN2, others are in advanced clinical development or have been clinically tested in a limited number of patients.…”

“…Often, efforts were focused on activity against the gatekeeper mutants (Dunna et al 2015, Ferreira et al 2015, Han et al 2016, Song et al 2016, Yoon et al 2016, 2017, Mologni et al 2017a,b, Wang et al 2017. Finally, in a completely different approach, Kumarasamy and Sun described the selective block of RET transcription by a G-quadruplex-stabilizing agent (Kumarasamy & Sun 2017).…”

Site Identification and Next Choice Protocol for Hit-to-Lead Optimization

“…In contrast, the hit-to-lead stage is expected to improve efficiency because it primarily exploits the trial-and-error approach of medicinal chemists . In the early hit-to-lead stage, an appropriate selection of reaction points and a set of substitutes are required. − Medicinal chemists must make the right choices because their choices affect the affinity of hit derivatives and the efficiency of the hit-to-lead stage. , Even if structural information on the protein–hit compound complex is available, making decisions is difficult because numerous parameters must be considered, including physicochemical properties, target selectivity, and synthetic accessibility . Therefore, a computational support tool for these decisions is required to improve the quality of lead compounds and the efficiency of the hit-to-lead stage.…”

Mono- and Diamination of 4,6-Dichloropyrimidine, 2,6-Dichloropyrazine and 1,3-Dichloroisoquinoline with Adamantane-Containing Amines

“…Amino substituted pyrimidines, pyrazines, and isoquinolines attract the researchers' interest due to their versatile biological activities stemming from the ability to form hydrogen bonds with various biomolecules, like nucleobases. Some derivatives of aminopyrimidine were found to act as inhibitors of various ferments: 1-phosphatidylinositol-3-phosphate 5-kinase (FAB1B) (e.g., bacimethrin) [1-3], 1-acyl-sn-glycerol-3-phosphate acyltransferase (plsC) [4], [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1 (PDHA1) (e.g., 6 -((6-aminopyrimidin-4-yl)amino)-8 -methyl-2 H-spiro[cyclohexane-1,3imidazo[1,5-a]pyridine]-1 ,5 -dione) [5], and perform as multitarget RET (rearranged during transfection) inhibitors [6]. In particular, substituted 4,6-diaminopyrimidines are capable of blocking epidermal growth factor receptor (EGFR), what make them perspective for the lung cancer treatment [7].…”