KRASG12C has emerged as a promising target
in the treatment
of solid tumors. Covalent inhibitors targeting the mutant cysteine-12
residue have been shown to disrupt signaling by this long-“undruggable”
target; however clinically viable inhibitors have yet to be identified.
Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99)
we identified in KRASG12C to identify inhibitors suitable
for clinical development. Structure-based design efforts leading to
the identification of a novel quinazolinone scaffold are described,
along with optimization efforts that overcame a configurational stability
issue arising from restricted rotation about an axially chiral biaryl
bond. Biopharmaceutical optimization of the resulting leads culminated
in the identification of AMG 510, a highly potent, selective, and
well-tolerated KRASG12C inhibitor currently in phase I
clinical trials (NCT03600883).
The innate immune signaling kinase, TBK1, couples pathogen surveillance to induction of host defense mechanisms. Pathological activation of TBK1 in cancer can overcome programmed cell death cues, enabling cells to survive oncogenic stress. The mechanistic basis of TBK1 prosurvival signaling, however, has been enigmatic. Here we show that TBK1 directly activates AKT by phosphorylation of the canonical activation loop and hydrophobic motif sites independently of PDK1 and mTORC2. Upon mitogen stimulation, triggering of the innate immune response, re-exposure to glucose, or oncogene activation, TBK1 is recruited to the exocyst, where it activates AKT. In cells lacking TBK1, insulin activates AKT normally, but AKT activation by exocyst-dependent mechanisms is impaired. Discovery and characterization of a 6-aminopyrazolopyrimidine derivative, as a selective low nanomolar TBK1 inhibitor, indicates this regulatory arm can be pharmacologically perturbed independently of canonical PI3K/PDK1 signaling. Thus, AKT is a direct TBK1 substrate that connects TBK1 to prosurvival signaling.
The Curtius rearrangement is a classic, powerful method for converting carboxylic acids into protected amines, but its widespread use is impeded by safety issues (the need to handle azides). We have developed an alternative to the Curtius rearrangement that employs a copper catalyst in combination with blue-LED irradiation to achieve the decarboxylative coupling of aliphatic carboxylic acid derivatives (specifically, readily available N-hydroxyphthalimide esters) to afford protected amines under mild conditions. This C–N bond-forming process is compatible with a wide array of functional groups, including an alcohol, aldehyde, epoxide, indole, nitroalkane, and sulfide. Control reactions and mechanistic studies are consistent with the hypothesis that copper species are engaged in both the photochemistry and the key bond-forming step, which occurs through out-of-cage coupling of an alkyl radical.
Proteolysis targeting chimeras (PROTACs) are bispecific molecules containing a target protein binder and an ubiquitin ligase binder connected by a linker. By recruiting an ubiquitin ligase to a target protein, PROTACs promote ubiquitination and proteasomal degradation of the target protein. The generation of effective PROTACs depends on the nature of the protein/ligase ligand pair, linkage site, linker length, and linker composition, all of which have been difficult to address in a systematic way. Herein, we describe a "click chemistry" approach for the synthesis of PROTACs. We demonstrate the utility of this approach with the bromodomain and extraterminal domain-4 (BRD4) ligand JQ-1 (3) and ligase binders targeting cereblon (CRBN) and Von Hippel-Lindau (VHL) proteins. An AlphaScreen proximity assay was used to determine the ability of PROTACs to form the ternary ligase-PROTAC-target protein complex and a MSD assay to measure cellular degradation of the target protein promoted by PROTACs.
Although tertiary phosphines have emerged as remarkably versatile nucleophilic catalysts, there has been only very limited progress in achieving asymmetric catalysis with chiral phosphines. In this report, the first highly enantioselective variant of the Kwon annulation of imines with allenes is described. Thus, C2-symmetric chiral phosphepine 1 serves as an effective catalyst for this powerful process, furnishing an array of functionalized piperidine derivatives with very good stereoselectivity.
[reaction: see text] 1-Nitro- and 1-cyano-cyclopropyl ketones have been prepared in an expedient manner from cyclopropanation reactions of alkenes by diazo compounds or in situ-generated phenyliodonium ylides catalyzed by Rh(II) carboxylates. The doubly activated cyclopropanes were used as synthetic precursors for the regiospecific synthesis of 4-nitro- and 4-cyano-dihydropyrroles upon treatment with primary amines. Oxidation of the dihydropyrroles with DDQ allows rapid access to densely functionalized pyrroles.
KRAS
regulates many cellular processes including proliferation,
survival, and differentiation. Point mutants of KRAS have long been
known to be molecular drivers of cancer. KRAS p.G12C, which occurs in approximately 14% of lung adenocarcinomas, 3–5%
of colorectal cancers, and low levels in other solid tumors, represents
an attractive therapeutic target for covalent inhibitors. Herein,
we disclose the discovery of a class of novel, potent, and selective
covalent inhibitors of KRASG12C identified through a custom
library synthesis and screening platform called Chemotype Evolution
and structure-based design. Identification of a hidden surface groove
bordered by H95/Y96/Q99 side chains was key to the optimization of
this class of molecules. Best-in-series exemplars exhibit a rapid
covalent reaction with cysteine 12 of GDP-KRASG12C with
submicromolar inhibition of downstream signaling in a KRASG12C-specific manner.
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