Development of Highly Potent and Selective Covalent FGFR4 Inhibitors Based on SNAr Electrophiles
Moritz SchwarzMaksym KurkunovFlorian WittlingerRamona RudalskaGuiqun WangMartin P. SchwalmAlexander RaschB.J. WagnerStefan LauferStefan KnappDaniel DauchMatthias Gehringer
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Fibroblast Growth Factor Receptor 4 (FGFR4) is thought to be a driver in several cancer types, most notably in hepatocellular carcinoma. One way to achieve high potency and isoform-selectivity for FGFR4 is covalently targeting a rare cysteine (C552) in the hinge region of its kinase domain that is not present in other FGFR family members (FGFR1-3). Typically, this cysteine is addressed via classical acrylamide electrophiles. We demonstrate that non-canonical covalent “warheads” based on nucleophilic aromatic substitution (SNAr) chemistry can be employed in a rational manner to generate highly potent and (isoform )selective FGFR4 inhibitors with a low intrinsic reactivity. Key compounds showed low- to subnanomolar potency, efficient covalent inactivation, and excellent selectivity over other FGFRs, kinases with an equivalent cysteine and a representative subset of the kinome. Moreover, these compounds achieved nanomolar potencies in cellular assays and demonstrated good microsomal stability highlighting the potential of SNAr-based approaches in covalent inhibitor design.Using appropriate sets of reference nucleophiles, the reactivity of neutral electrophiles of widely different reactivity and structure has been ranked on the comprehensive electrophilicity scale of Mayr (Acc. Chem. Res., 2003, 36, 66), holding promise of a general rationalization of σ-complexation processes and related SNAr substitutions.
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Abstract The anion, generated in situ from the N‐silyltrifluoroethoxyphosphoranimine (I) and BuLi, reacts with the electrophiles (II) to give the phosphoranimine derivatives (III).
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The first-generation development route used to prepare the PI3Kδ inhibitor GNE-293 (3) for early toxicology studies is described. Through the use of a metal-free SNAr reaction in place of a Pd-catalyzed C–N coupling, the synthesis was both simplified and made more reproducible in preparation for scale-up by reducing the number of operations required for purification and eliminating the need for column chromatography. The utility of the recently developed reagent TMPZnCl·LiCl is highlighted by a novel method of iodination to access the key aryl halide intermediate.
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Fused-ring systems containing heterocycles are attractive templates for drug discovery. Biologically active 6-5-5+6 fused-ring systems that possess heterocycles are available, but these require a relatively large number of synthetic steps for preparation. Therefore, pyrazolofuropyrazine was designed as a 6-5-5+6 ring system template that incorporates ready accessibility for drug discovery. Pyrazolofuropyrazines were successfully constructed in only a few steps via one-pot SNAr reaction/intramolecular C–H direct arylation. As a drug candidate, pyrazolofuropyrazine has earned a favorable LogP, although significant biological activity has yet to be established; the ready accessibility of pyrazolofuropyrazine template, however, offers an opportunity for the rapid development of promising new drug candidates.
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