Targeting Protein-Protein Interactions

Protein-protein interactions govern cellular signaling and drug responses. Photocatalytic proximity labeling uses light-activated iridium or xanthene photocatalysts linked to targeting modalities to generate reactive species that tag proximal proteins, enabling high-resolution mapping of protein neighborhoods in living cells by MS proteomics. This talk will discuss how the approach has been used to validate small-molecule target engagement, elucidate protein degrader mechanisms, and reveal previously hidden disease-relevant interactions, accelerating discovery of next-generation therapeutics.

MOMA-341 is a distinct, potent and selective clinical stage covalent inhibitor of WRN. Covalent series optimization was based on refinement of covalent warhead trajectory, compound rigidity, and improvement of binding affinity to drive high kinact/KI.  Further refinement of potency and ADME properties, guided by in vivo target occupancy prediction, led to the discovery of MOMA-341, which demonstrates robust tumor regression in mouse xenograft models and is in clinical development.

The allure of testing compound libraries comprising clinically used drugs is compelling: your screening hit is already FDA-approved and hence can be repurposed to serve your new target along with its associated indication to progress straight into patients. Not only is this fraught notion rife with errors, but, as we now describe, we have identified with statistical proof the more concerning phenomenon that widely used drug repurposing libraries are disproportionately populated by promiscuous compounds, destined to lead nowhere and waste precious resources.

Phase 1 clinical candidate HLD-0915, a Regulated Induced Proximity Targeting Chimera (RIPTAC) Therapeutic, is a heterobifunctional small molecule that leverages full-length AR expression in tumor cells to form a cooperative trimeric complex with AR and BRD4, resulting in BRD4 loss of function in mCRPC cells and a potent antitumor effect. HLD-0915 activity requires only presence, not driver status, of FL-AR and retains activity in models of anti-androgen therapy resistance settings.

This presentation will discuss the RapaGlue platform, a novel non-degrading macrocyclic molecular glue that have been found to modulate several hard to drug target classes.  New ternary X-Ray crystal structures for TRDD and TRAF2 will be presented showing unique binding modes for PPI disruption. An analysis of the RapaGlue DNA-encoded library for showing diverse binding across transcription factors, GSTP1, TRADD and TRAF2 will be compared. Our progress in integrated AI/ML methods, structural data to provide an SAR strategies for improving molecular binding and drug like properties will be discussed.

Tauopathies are characterized by the formation of tau protein-based neurofibrillary tangles which impede neuronal function. Here, we sought to identify new targets to address tauopathies, through a phenotypic screen using a cellular model of tau-aggregate clearance. An optimized analogue derived from this effort induced aggregate clearance in multiple models of hTauP301L aggregation at nanomolar concentrations. Chemoproteomic studies implicated protein disulfide isomerase 1 (P4HB), as a candidate target.

The use of small molecule induced proximity to understand and potentially treat neurodegenerative diseases holds significant potential. Targeted Protein Degrader molecules are having growing clinical impact with recent examples of CNS active Proteolysis Targeting Chimeras entering Phase 1 trials. Nevertheless, paths to prospectively identify and profile such molecules for CNS application remains underexplored. During my talk, I will discuss how we have approached the discovery of chemistries to aid the exploration of CNS-compliant chemical space for induced proximity modalities and key learnings in in the profiling of hit compounds from cellular to in vivo proof of concept.

An analysis 104 small molecule oral drugs approved by the FDA from 2020-2024 was conducted on approved dose, human pharmacokinetics, safety and DDIs.  This analysis highlights several successful drugs with properties that may be considered outside the range of typical drugs, such as high dose, high clearance or low oral bioavailability.  These insights may help scientists to understand which risks may be acceptable to developing small molecule drugs.

Efforts for covalent targeting non-cysteine mutants like KRASG12D have been hampered by the lack of suitable electrophiles. The development of ß-lactone warheads has enabled structure-guided design and optimization of covalent aspartate-reactive inhibitors. X-ray crystallography and quantum chemical calculations of transition-state barrier heights have been employed to establish structure-activity and -stability correlations with the goal of broadening the use of aspartate covalency and substituted ß-lactones as chemoselective electrophiles in medicinal chemistry.

We developed a platform of RAS(ON) tri-complex inhibitors that bind cyclophilin A (CYPA). The resulting binary complex engages RAS(ON), forming a tri-complex that sterically inhibits RAS interaction with its downstream effectors. We generated multiple RAS(ON) mutant-selective and multi-selective inhibitors. We will discuss the G12D- and G12V-selective inhibitors zoldonrasib (RMC-9805) and RMC-5127, respectively. These inhibitors suppress RAS pathway signaling and induce tumor regressions in KRAS mutant human xenograft models in mice.