Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors.

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).

Ligand-Controlled Diastereoselective 1,3-Dipolar Cycloadditions of Azomethine Ylides with Methacrylonitrile.

Copper-catalyzed reactions of glycine ester arylimines and methacrylonitrile provide selective access to either the endo or exo pyrrolidine cycloadducts. DFT calculations have elucidated the origins of ligand-controlled diastereoselectivity.

Tricyclic Analogues of Epidithiodioxopiperazine Alkaloids with Promising In Vitro and In Vivo Antitumor Activity.

Epipolythiodioxopiperazine (ETP) alkaloids are structurally elaborate alkaloids that show potent antitumor activity. However, their high toxicity and demonstrated interactions with various biological receptors compromises their therapeutic potential. In an effort to mitigate these disadvantages, a short stereocontrolled construction of tricyclic analogues of epidithiodioxopiperazine alkaloids was developed. Evaluation of a small library of such structures against two invasive cancer cell lines defined initial structure-activity relationships (SAR), which identified 1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine 3c and related structures as particularly promising antitumor agents. ETP alkaloid analogue 3c exhibits low nanomolar activity against both solid and blood tumors in vitro. In addition, 3c significantly suppresses tumor growth in mouse xenograft models of melanoma and lung cancer, without obvious signs of toxicity, following either intraperitoneal (IP) or oral administration. The short synthesis of molecules in this series will enable future mechanistic and translational studies of these structurally novel and highly promising clinical antitumor candidates.

Synthesis of cyclopentenimines from N-allyl ynamides via a tandem aza-Claisen rearrangement-carbocyclization sequence.

We describe here details of our investigations into Pd-catalyzed and thermal aza-Claisen-carbocyclizations of N-allyl ynamides to prepare a variety of α,ß-unsaturated cyclopentenimines. The nature of the ynamide electron-withdrawing group and ß-substituent plays critical roles in the success of this tandem cascade. With N-sulfonyl ynamides, the use of palladium catalysis is required, as facile 1,3-sulfonyl shifts dominate under thermal conditions. However, since no analogous 1,3-phosphoryl shift is operational, N-phosphoryl ynamides could be used to prepare similar cyclopentenimines under thermal conditions through zwitter ionic intermediates that undergo N-promoted H-shifts. Alternatively, by employing ynamides bearing tethered carbon nucleophiles, the zwitter ionic intermediates could be intercepted, giving rise rapidly to more complex fused bi- and tricyclic scaffolds.

An intramolecular [2 + 2] cycloaddition of ketenimines via palladium-catalyzed rearrangements of N-allyl-ynamides.

A cascade of Pd-catalyzed N-to-C allyl transfer-intramolecular ketenimine-[2 + 2] cycloadditions of N-allyl ynamides is described. This tandem sequence is highly stereoselective and the [2 + 2] cycloaddition could be rendered in a crossed or fused manner depending on alkene substitutions, leading to bridged and fused bicycloimines.

Carbocyclization cascades of allyl ketenimines via aza-Claisen rearrangements of N-phosphoryl-N-allyl-ynamides.

A series of carbocyclization cascades of allyl ketenimines initiated through a thermal aza-Claisen rearrangement of N-phosphoryl-N-allyl ynamides is described. Interceptions of the cationic intermediate via Meerwein-Wagner rearrangements and polyene-type cyclizations en route to fused bi- and tricyclic frameworks are featured.

Introducing a new class of N-phosphoryl ynamides via Cu(I)-catalyzed amidations of alkynyl bromides.

We describe here the first synthesis of N-phosphoryl ynamides featuring C- and P-chirality via copper(I)-catalyzed amidative cross-couplings between phosphoramidates and phosphordiamidates with alkynyl bromides. Also featured is a tandem aza-Claisen-hetero-[2+2] cycloaddition for the synthesis of N-phosphoryl azetidin-2-imines.

An efficient and practical entry to 2-amido-dienes and 3-amido-trienes from allenamides through stereoselective 1,3-hydrogen shifts.

Preparations of de novo acyclic 2-amido-dienes and 3-amido-trienes through 1,3-hydrogen shifts from allenamides are described. These 1,3-hydrogen shifts could be achieved thermally or they could be promoted by the use of Brønsted acids. Under either condition, these processes are highly regioselective in favour of the α-position, and highly stereoselective in favour of the E-configuration. In addition, 6π-electron electrocyclic ring-closure could be carried out with 3-amido-trienes to afford cyclic 2-amido-dienes, and such electrocyclic ring-closure could be rendered in tandem with the 1,3-hydrogen shift.

Stereoselective 6π-electron electrocyclic ring closures of 2-halo-amidotrienes via a remote 1,6-asymmetric induction.

A diastereoselective 6π-electrocyclic ring closure employing halogen-substituted 3-amidotrienes via a 1,6-remote asymmetric induction is described. This new asymmetric manifold for pericyclic ring closure further underscores the significance of the allenamide chemistry.