RMC-9805 is a first-in-class, covalent KRAS(G12D)(ON) molecular glue inhibitor from Revolution Medicines that uses a cyclophilin A (CypA)-recruiting tricomplex mechanism combined with a finely tuned aziridine covalent handle to inhibit the previously “undruggable” KRAS(G12D) mutant. Read our coverage of the discovery story, disclosed at the AACR 2024 meeting in San Diego, to discover how structural and modeling insights were key to engaging a poorly nucleophilic mutant Asp, how RMC-9805 synergizes with PD-1 inhibitors, and the progress this remarkable compound is making in the clinic.

RMC-6236 is a non-covalent pan-RAS(ON) inhibitor from Revolution Medicines, which shows remarkable efficacy in tumors driven by RAS mutants that were previously considered “undruggable,” such as G12V/D/A/S, G13X, and Q61X. RMC-6236 exerts its action via a “tri-complex” mechanism, gluing RAS to the ubiquitously expressed chaperone protein, cyclophilin A. Our in-depth article covers the presentation given at the AACR 2024 meeting, which outlines the discovery and preclinical profile of RMC-6236 as well as the latest clinical updates.

The accelerated approvals of Ras(OFF)-targeting KRAS G12C inhibitors sotorasib and adagrasib, decades in the making, marked the beginning of a new phase of KRAS drug discovery. While an increasing number of follow-on KRAS inhibitors are emerging with similar mechanisms of action, Revolution Medicines’ 2023 Molecule of the Year Nominee, RMC-6291, is representative of a completely novel approach that could become a strong addition to the clinical toolbox for KRAS, but also serves as proof-of-concept for a new class of small molecule therapeutics entirely.

GS-6207 is an HIV-1 inhibitor that acts on the capsid protein monomer (p24), which normally self-assembles in the HIV virion to form the capsid core that is essential for virus infectivity. GS-6207 targets a protein-protein interaction between the small (24 kDa) p24 monomers, binding in a glue-like fashion to two separate monomers, and is [...]

Zunsemetinib (ATI-450, CDD-450) is a p38α- MK2 complex inhibitor discovered by Confluence Technologies and developed by Confluence spinout, Aclaris Therapeutics. The molecule has a unique molecular glue-like mechanism of action that held promise in immunology, but sadly recent results have led to its discontinuation. This article reviews the target, its mechanism, and why it mattered.

Since the 2014 discoveries that thalidomide-like compounds “glue” together the cereblon (CRBN) unit of the ubiquitin E3 ligase complex and certain immune cell transcription factors, molecular glue degraders have been caught up in the targeted protein degradation zeitgeist that catapulted PROTACs , their bulkier bivalent counterparts, to the [...]

The Lilly glucagon-like peptide-1 receptor (GLP-1R) agonist ( LSN3318839 ) is a positive allosteric modulator intended to treat type 2 diabetes. This drug candidate has an interesting proposed mechanism as a molecular glue between GLP-1R and GLP peptide, enhancing endogenous peptide activity. GLP-1 agonism is a well-established mechanism for [...]

The Revolution Medicines KRASG12C inhibitor, RM-018, “glues” KRASG12C to the highly abundant chaperone protein, cyclophilin A, in a tri-complex (KRAS- inhibitor-cyclophilin A) stabilized by protein-protein interactions. An undisclosed molecule in their pipeline with a related mechanism, RMC-6291 , has been reported to be orally bioavailable [...]

The Bristol Myers Squibb (BMS)/Celgene GSPT1 degrader (CC-90009) is a CRBN-based molecular glue (CELMoD). It is a clinical candidate in Ph. I for AML and MDS, and in contrast to CC-92480 highlighted last March, spares the primary targets of prior imide drugs (IKZF1/3) and instead selectively degrades GSPT1 ( a target previously identified [...]

GS-6207 is an HIV-1 inhibitor that acts on the capsid protein monomer (p24), which normally self-assembles in the HIV virion to form the capsid core that is essential for virus infectivity. GS-6207 targets a protein-protein interaction between the small (24 kDa) p24 monomers, binding in a glue-like fashion to two separate monomers, and is [...]

( R )-CR8 is a known CDK inhibitor that was recently discovered to be a molecular glue-type degrader of cyclin K. A crystal structure of an E3 component-CR8-CDK12-cyclin K complex shows that CR8 acts by binding to the active site of a CDK (which binds to cyclin K), and recruiting an E3 component through a solvent-exposed lipophilic moiety on [...]

We asked the global drug discovery community to vote on their favorite molecule from 2020, and the results are in. The community’s 2020 choice for Small Molecule of the Year is GS-6207 (lenacapavir), the awe-inspiring HIV capsid inhibitor published by Gilead Sciences in a 2020 issue of Nature.