KRAS G12C inhibitors targeting the GDP-bound inactive state face potential resistance, making the GTP-bound active state a compelling, underexplored target. We developed novel a-fluoro, ß-heteroaryl acrylamide warheads that covalently engage Cys12 via vinylogous nucleophilic aromatic substitution, accommodating both nucleotide states through the Switch II pocket. Systematic SAR—guided by linker geometry, electrophilicity, and heterocycle basicity—yielded dual-state inhibitors with rapid cellular target engagement and faster KRAS G12C-RAF disruption kinetics than inactive-state-selective comparators.

We designed a series of natural product-inspired molecules that bind and remodel the surface of cyclophilin A (CYPA) to create a binary complex with high affinity for the active, GTP bound (ON) state of RAS. The resulting tri-complex sterically blocks RAS-effector interactions to disrupt downstream signaling. Structure-guided optimization enabled the development of the oral RAS(ON) G12D-selective, covalent, tri-complex inhibitor zoldonrasib (RMC-9805), which displays profound antitumor activity in preclinical models.

VRK1 has emerged as a paralog-selective synthetic lethal target in cancers with low VRK2 expression, including nearly all neuroblastomas and over 60% of glioblastomas. We describe complementary hit-discovery and lead-generation approaches, including covalent MS-based profiling, to identify potent and selective VRK1 inhibitors. These efforts are supported by robust biochemical and biophysical assays, high-resolution crystal structures, and cellular functional studies, establishing VRK1 as a tractable, structurally enabled target.

Many of the most relevant therapeutic proteins have not been successfully targeted with traditional small molecules. At GSK we combine DNA-Encoded Library technology (DEL) with unique covalent library design and screening to target reactive residues on challenging proteins. Our covalent strategies enable ID of reactive pockets and prioritization of molecules with unique MoAs. These screens serve to expand small-molecule discovery toward higher therapeutic impact across a range of modalities.

Molecular glues that form inhibitory ternary complexes between FKBP12 or CYPA and target proteins (rapamycin/FK506 and daraxonrasib/cyclosporine) have been used clinically. However, the systematic discovery of molecular glues against proteins of interest has been limited. We constructed and screened a multi-million compound DEL, biased to bind and resurface FKBP12, against a set of 25 purified protein targets. Hits were characterized in biophysical and cellular assays with the targets BRD9 and QDPR.

IR-MALDESI-MS is a versatile uHT-MS platform developed at AbbVie that can perform high-resolution MS analysis at rates of >1 sample per second from complex matrices. This platform is highly valuable for hit-generation campaigns and beyond, enhancing the efficiency of small molecule lead discovery. In this presentation, I will discuss the development and applications of novel assays using IR-MALDESI-MS technology.

DNA encoded focused library has became an efficient strategy for hit identification and hit to lead optimization for specific target protein. However, the design and synthesis of target focused library is still a challenge for many protein targets. Integrating DEL with chemoproteomics could be an effective and practicable strategy for the target focused library technology development. This talk will highlight recent advancement of the technology integration between DEL and other drug discovery technologies such as FBDD and chemoproteomics for the reversible and covalent Inhibitors discovery. 

Biased ligand design lacks a specification step. Structural data separating Gs-coupled from arrestin-coupled receptor states is scarce, and nearly absent for class B1, so there is little substrate on which to train a bias classifier. We use a receptor-level proxy instead. A classifier trained on active versus inactive states yields saliency that recovers known activation biology. That validated signal lets us localize structural refinement to selected regions, including arrestin-associated ones, while measuring retained activation. Ligand generation is then conditioned on the resulting whole-receptor structure. DEEP DISCOVERY (U.S. Patents 12,450,409 and 12,424,300), with GLP-1R as the worked example.

Biased signaling holds promise for discovering safer and more effective GPCR-targeted therapeutics, yet its reliable quantification remains challenging. Multiple experimental parameters, including pathway amplification and system bias, can distort measurements of ligand efficacy and bias. To address this, we developed a novel signaling platform that quantifies G protein activation and efficacy in real-time without amplification. This enables a more accurate comparison of ligand responses across pathways and systems. We demonstrate the utility of this system in profiling ligands at orphan GPCRs, including GPR75, providing new opportunities to deconvolute signaling bias and accelerate drug discovery in complex physiological and disease-relevant contexts.

Designer GPCR partial agonists enable precise modulation of receptor activity, allowing for the development of safer and more effective treatments. By targeting novel allosteric pockets, we developed low-efficacy µ-opioid receptor agonists that reduce side effects and withdrawal symptoms associated with current drugs. This strategy provides a blueprint for rational efficacy control by "fine-tuning" these interactions across GPCR targets, potentially transforming therapies for pain and other conditions.

BAPC (Biased Agonist Pharmacochaperone) represents a differentiated small-molecule strategy designed to overcome key limitations of conventional MC4R agonists. This novel modality uniquely combines three complementary pharmacological properties: dual MC4R/MC3R activity to maximize therapeutic efficacy, functional bias away from ß-arrestin signaling to limit receptor internalization and sustain receptor activation, and pharmacochaperone activity to enhance membrane trafficking and surface expression of both wild-type and mutant receptors. This integrated mechanism has the potential to address both common and MC4R mutation-associated obesity. Consistent with this rationale, lead compounds demonstrated sustained reductions in food intake and weight gain in DIO rodent models, validating the therapeutic promise of the approach.

The delta opioid receptor is considered a promising alternative target for pain therapeutics that can avoid many of the adverse side effects associated with traditional opioids. Using structural biology, pharmacology, and single-molecule fluorescence techniques, we show how different molecules stabilize distinct receptor states that control signaling. These insights help explain why some compounds activate the receptor effectively while others block it and provide a framework for designing improved therapeutics.

Developing “binding first” methods to identify chemical matter for GPCRs is an emerging need in drug-discovery efforts, especially when targeting an orphan GPCR where functional activity has not yet been determined. Development of new solubilization techniques for GPCRs has helped overcome some of the challenges we face when trying to work with detergent-solubilized targets. Using 19F-NMR and SPR, we identified and optimized fragment binders for an orphan GPCR.

Lipid nanodiscs provide a well-defined and tunable platform for dissecting the contributions of phospholipids and cholesterol to GPCR conformational equilibria.  We present data from an integrative structural biology approach that define how lipids modulate GPCR conformational landscapes and regulate the formation of signaling complexes.  We then describe how insights obtained from this research have led us to develop NMR-based methodologies for quantifying drug efficacy that address key limitations of conventional cell-based pharmacological assays.

DNA-encoded libraries (DELs) utilized in ternary-complex affinity selections enable the identification of chemical entities independent of functional mechanisms of action. This presentation will discuss the use of DELs in discovering molecular glues and their varied effects across distinct biological contexts. The performance of both biased and naïve DELs, along with their respective results, will also be addressed.

Primary DNA-encoded library (DEL) screens identify binders from millions of related compounds, but translating sequencing readouts into actionable SAR requires a systematic approach. This talk describes a practical method for extracting positive and negative SAR directly from primary DEL data and applying it to early hit optimization. Case studies illustrate the approach, which is implemented in a web-based platform integrating DEL SAR and analyses for early, data-driven decision-making.

Selective inhibition of homologous proteins remains a key challenge in small-molecule drug discovery. Using parallel DNA-encoded library selections against PGK2 and ubiquitously expressed 88% identical PGK1, we identified selective PGK2 binders. Off-DNA synthesis yielded potent, isoform-selective inhibitors consistent with enrichment profiles. These compounds are readily optimized into lead candidates, highlighting DEL chemical diversity and the effectiveness of parallel selections for discovering isoform-selective ligands and developable chemical probes.

By removing the synthesis bottleneck associated with traditional hit-to-lead optimization, high-throughput synthesis and direct-to-biology (D2B) screening accelerates the discovery of drug candidates with first-in-class structures and mechanisms. Building on the success of D2B implemented at Carmot Therapeutics, we present Kimia’s ATLAS platform, a next-generation D2B and direct-to-ADME (D2A) platform that integrates multiple chemistries and machine learning to guide the search for novel drugs, exemplifying the approach with several case studies.

EP4 agonists are of interest for the treatment of inflammatory bowel disease but can cause undesired effects outside of the intestines. Our program to discover minimally systemically exposed EP4 agonists utilized a direct-to-biology platform to enable rapid exploration of chemical space and the identification of BMS-986526, a lead that was nominated as a development candidate. This presentation will cover the execution of our direct-to-biology campaign and the profile of BMS-986526.

Targeting PPIs that are either unstructured or "flat” is a challenge. We use Gasdermin-D (GSDMD) as a case study to demonstrate that transition metal ions can be used to identify novel sites that can disrupt PPIs. Using biochemical and cellular assays, DLS, nanoDSF and cryoEM, we show that GSDMD is inhibited by Ni(II) coordination complexes, uncovering a novel binding site with key insights gained from site-directed mutagenesis.

Purines bind a large fraction of the proteome, yet most purine-binding pockets remain under-explored for ligand discovery. We developed SuPUR (sulfonyl-purine) chemoproteomics to map the human-SuPUR interactome, capturing 31,000+ targetable tyrosine and lysine sites, representing a rich binding map for enabling ligand discovery programs. SuPUR ligands can bind in a regioselective manner to yield nanomolar, proteome-selective modulators of enzymes and protein-protein interactions. A site-specific ACAT2 ligand exposed a metabolic vulnerability in cancer, with a co-crystal structure guiding further design.

There is no clear consensus on what drives DEL selection, equilibrium or kinetics of ligand binding. A better understanding of the mechanism of DEL selection should help better design or trouble shoot DEL strategy, in particular for DEL aiming at glue molecules.