ABSTRACT
HER2 overexpression and amplification have been identified as oncogenic drivers, and the development of therapies to treat tumors harboring these markers has received considerable attention. Activation of HER2 signaling and subsequent cell growth can also be induced by HER2 mutations, including the common YVMA insertion in exon 20 within the kinase domain. Enhertu is currently the only approved treatment for HER2 mutant tumors in NSCLC. TKIs tested in this space have suffered from off-target activity, primarily due to EGFRWT inhibition or attenuated activity against HER2 mutants. The goal of this work was to identify a TKI that would provide robust inhibition of oncogenic HER2WT and HER2 mutants while sparing EGFRWT activity. Herein, we describe the development of a potent, covalent inhibitor of HER2WT and the YVMA insertion mutant while providing oral bioavailability and avoiding the inhibition of EGFRWT.
Subject(s)
Protein Kinase Inhibitors , Receptor, ErbB-2 , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-2/metabolism , Humans , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Animals , Drug Discovery , Mutation , Cell Line, Tumor , Structure-Activity Relationship , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Mice , Rats , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolismABSTRACT
We describe a total synthesis of the rare isocyanoterpene natural product isoneoamphilectane and two of its unnatural diastereomers. The significantly strained ring system of the reported natural productâalong with a hypothesis about a biosynthetic relationship to related family membersâinspired us to consider a potential misassignment in the structure's relative configuration. As a result, we initially targeted two less strained, more accessible, stereoisomers of the reported natural product. When these compounds failed to exhibit spectroscopic data that matched those of isoneoamphilectane, we embarked on a synthesis of the originally proposed strained structure via an approach that hinged on a challenging cis-to-trans decalone epimerization. Ultimately, we implemented a novel cyclic sulfite pinacol-type rearrangement to generate the strained ring system. Additional features of this work include the application of a stereocontrolled Mukaiyama-Michael addition of an acyclic silylketene acetal, an unusual intramolecular alkoxide-mediated regioselective elimination, and an HAT-mediated alkene hydroazidation to forge the C-N bond of the tertiary isonitrile. Throughout this work, our synthetic planning was heavily guided by computational analyses to inform on key issues of stereochemical control.
ABSTRACT
Soft enolization conditions are revealed to be markedly better than the typically applied hard enolization protocols for regioselective enoxysilane formation from unsymmetrical 3-substituted cycloalkanones. Five-, six-, and seven-membered cycloalkanones each with 3-methyl, 3-isopropyl, or 3-phenyl substituents were investigated, and in all but one case, regioselectivities were ≥11:1 for enolization away from the substituent. These results are complementary to the regiospecific enoxysilane formation derived from cycloalkenone conjugate addition/enolate silylation.
Subject(s)
AlcoholsABSTRACT
A new chiral auxiliary for the diastereoselective alkylation of amino ester enolates that takes advantage of chiral information stored on the enolate side of the amino ester substrate has been developed. Chiral α-sulfinamido esters were alkylated under basic conditions in good yields (up to 90%) and good to high diastereoselectivities (generally >6:1) to provide unnatural mono- and α,α-disubstituted amino acid derivatives. This auxiliary allowed for the ready conversion of ester functionality without the need for esoteric reagents. Furthermore, the auxiliary is easily removed to provide enantiopure amino acids. Computational studies revealed that a chelated transition state governs electrophile addition from the convex face of a transient bicyclic intermediate. This method allows ready access to enantioenriched natural and unnatural amino acids.
