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Molecular glue degraders (MGDs) are small molecules that facilitate proximity between a target protein and an E3 ubiquitin ligase, thereby inducing target protein degradation. Glutarimide-containing compounds are MGDs that bind cereblon (CRBN) and recruit neosubstrates. Through explorative synthesis of a glutarimide-based library, we discovered a series of molecules that induce casein kinase 1 alpha (CK1α) degradation. By scaffold hopping and rational modification of the chemical scaffold, we identified an imidazo[1,2- a ]pyrimidine compound that induces potent and selective CK1α degradation. A structure-activity relationship study of the lead compound, QXG-6442 , identified the chemical features that contribute to degradation potency and selectivity compared to other frequently observed neosubstrates. The glutarimide library screening and structure-activity relationship medicinal chemistry approach we employed is generally useful for developing new molecular glue degraders toward new targets of interest.

Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging. We report here an approach to glutarimide-containing molecular glue synthesis using multicomponent reactions as a central modular core-forming step. Screening the resulting library identified HRZ-1 derivatives that target casein kinase 1 α (CK1α) and Wee-like protein kinase (WEE1). Further medicinal chemistry efforts led to identification of selective monovalent WEE1 degraders that provide a potential starting point for the eventual development of a selective chemical degrader probe. The structure of the hit WEE1 degrader complex with CRBN-DDB1 and WEE1 provides a model of the protein-protein interface and ideas to rationalize the observed kinase selectivity. Our findings suggest that modular synthetic routes combined with in-depth structural characterization give access to selective molecular glue degraders and expansion of the CRBN-degradable proteome.

Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While Cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging. We report here an approach to glutarimide-containing molecular glue synthesis using multicomponent reactions as a central modular core-forming step. Screening the resulting library identified HRZ-01 derivatives that target casein kinase 1 alpha (CK1α) and Wee-like protein kinase (WEE1). Further medicinal chemistry efforts led to identification of selective monovalent WEE1 degraders that provide a potential starting point for the eventual development of a selective chemical degrader probe. The structure of the hit WEE1 degrader complex with CRBN-DDB1 and WEE1 provides a model of the protein-protein interface and a rationale for the observed kinase selectivity. Our findings suggest that modular synthetic routes combined with in-depth structural characterization give access to selective molecular glue degraders and expansion of the CRBN-degradable proteome.

Among base metals used for C-H activation reactions, chromium(III) is rather unexplored despite its natural abundance and low toxicity. We report herein chromium(III)-catalyzed C(sp 2 )-H functionalization of an ortho -position of aromatic and α,β-unsaturated secondary amides using readily available AlMe 3 as a base and using bromoalkynes, allyl bromide, and 1,4-dihydro-1,4-epoxynaphthalene as electrophiles. This redox-neutral reaction taking place at 70-90 °C, requires as low as 1-2 mol % of CrCl 3 or Cr(acac) 3 as a catalyst without any added ligand, and tolerates functional groups such as aryl iodide, boronate, and thiophene groups. Stoichiometric and kinetics studies as well as kinetic isotope effects suggest that the catalytic cycle consists of a series of thermally stable but reactive intermediates bearing two molecules of the amide substrate on one chromium atom and also that one of these chromate(III) complexes takes part in the alkynylation, allylation, and naphthalenation reactions. The proposed mechanism accounts for the effective suppression of methyl group delivery from AlMe 3 for ortho -C-H methylation.

Reactions of Ph3GePCO with KP(t-Bu)2 and Ph3SiCl, or direct reaction with Ph3SiP(t-Bu)2 provides the (Z)- and (E)-isomers of the phosphaalkene (t-Bu2)PC(OSiPh3)P(GePh3) 2, respectively. These isomers interconvert thermally and photochemically, while 2 also undergoes silyl and phosphide exchange with silylphosphines, consistent with a mechanism involving the reversible silylphosphination of Ph3GePCO.

The phosphaketene Ph 3 GePCO is shown to react with the phosphide KP(tBu) 2 to generate the anion [Ph 3 GePC(O)P(tBu) 2 ] - 1. This species reacts with CH 3 I or ClGePh 3 to give the dissymmetric diphospha-ureas (tBu) 2 PC(O)P(GePh 3 )(CH 3 ) 2 and (Ph 3 Ge) 2 PC(O)P(tBu) 2 3 respectively. Sequential treatment of 2 with a base and CH 3 I affords a route to (tBu) 2 PC(O)P(CH 3 ) 2 5. These species are products of the first modular diphospha-urea synthesis. The subsequent thermal and photochemical reactivity of these species was also probed and described., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)