bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.11.01.763478

Fragment Covalent Bond Formation at SOS1 Tyr-884 Inhibits KRAS Nucleotide Exchange

Bum-Erdene, K.·Gonzalez-Gutierrez, G.·Ghozayel, M. K.·Meroueh, S.
View original source ↗Export metadata ↓

Abstract

The activation of the KRAS oncogene from its inactive GDP-bound state to its active GTP-bound state is mediated by Son of Sevenless (SOS) exchange factors. Small-molecule inhibition of SOS1 has been achieved, with three compounds currently in clinical trials. These compounds bind to SOS1 and disrupt a crucial interaction between SOS1 Tyr-884 and KRAS Arg-73. Here, we screen libraries of aryl sulfonyl fluorides to explore covalent bond formation at Tyr-884 as a strategy for covalent inhibition of SOS1-KRAS binding. Initially, ten fragments were tested and several inhibited KRAS nucleotide exchange by SOS1. X-ray crystal structures revealed that one reaction site for the fragments was Tyr-884, but mass spectrometry and nucleotide exchange assays with wild-type and mutant SOS1 indicated additional reaction sites. To identify candidates specific to Tyr-884, we conducted a larger screen and identified fragment 11 (SOF-599). The fragment formed an adduct predominantly at Tyr-884 and inhibited KRAS nucleotide exchange by SOS1 in a time- and concentration-dependent manner. Fragment 11 (SOF-599) exhibited a half-maximal inactivation concentration (KI) of 12 micromolar and a reaction half-life of 6 h. These findings establish 11 (SOF-599) as a promising starting point for the development of covalent SOS1 inhibitors as an alternative strategy to existing non-covalent antagonists.

Explore related subjects

pharmacology and toxicologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Bum-Erdene, K., Gonzalez-Gutierrez, G., Ghozayel, M. K., Meroueh, S.. 2026-11-04. Fragment Covalent Bond Formation at SOS1 Tyr-884 Inhibits KRAS Nucleotide Exchange. https://doi.org/10.64898/2026.11.01.763478

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

The collective effect of non-nicotine constituents on the reinforcing and neuropharmacological effects of comprehensive cigarette smoke and electronic nicotine delivery system (ENDS) aerosol extracts in rats.

Tobacco product extracts containing nicotine and non-nicotine constituents are useful for understanding the collective role of these constituents in tobacco use disorder (TUD). However, few studies have used extracts with both water-soluble and non-water-soluble constituents with accompanying chemical analysis, or compared behavioral and neuropharmacological effects across product types. To address these limitations, we compared the relative abuse liability of cigarette smoke (CS) and electronic nicotine delivery system (ENDS) aerosol (EA) extracts to nicotine alone using intravenous self-administration in rats, and examined effects on nucleus accumbens (NAc) dopamine (DA) release and binding/function at nicotinic acetylcholine receptors (nAChRs) and other addiction-related receptors in vitro. CS extract contained higher levels of several behaviorally active non-nicotine constituents than EA extract. Both extracts produced a downward/leftward shift in the descending limb of the unit dose-response curve relative to nicotine alone, while only CS extract produced greater compensatory increases in responding compared to nicotine alone. Demand intensity (Q0) was lower for CS but not EA extract, relative to nicotine alone, whereas demand elasticity for both extracts was similar to nicotine alone. Stress-induced reinstatement was comparable between CS extract and nicotine alone but attenuated for EA extract. CS extract, but not EA extract, showed greater potency for 4{beta}2 nAChR activation and substantial binding across numerous non-nAChRs (DA, serotonergic, opioid) relative to nicotine alone at a high screening concentration. CS extract, but not nicotine alone, also inhibited cyclooxygenase (COX)-1 and -2 at smoking-relevant concentrations. There was no difference in NAc DA release between formulations. These findings indicate non-nicotine constituents contribute to certain reinforcing and neuropharmacological effects of CS, and to a lesser extent EA. Our finding of COX inhibition by CS extract warrants further investigation as a potential mechanism contributing to the effects of CS and TUD.

pharmacology and toxicology↗
bioRxiv2026

Complementary chemical and effect-based risk assessments reveal ecotoxicological risks in Caribbean coastal bays and coral reefs

Anthropogenic chemical pollution poses a significant, yet often unquantified threat to coral reef ecosystems. This study investigated the occurrence, dispersal, and ecotoxicological risks of chemical mixtures in three inland bays of Curacao (Southern Caribbean) and adjacent coral reefs during wet and dry seasons. Passive sampler extracts were analyzed with targeted chemical analysis and effect-based methods. Inland bays acted as reservoirs for chemical pollution, each exhibiting a unique chemical fingerprint likely linked to surrounding land use. Targeted chemical concentrations were higher during the wet season, particularly inside the bays, indicating rainfall-driven mobilization of terrestrial contaminants. Many compounds exceeded their predicted no-effect concentrations, while mixture toxic pressure was low to moderate and highest inside the bays. In contrast, bioassays integrating the effects of the entire mixture revealed a potential ecotoxicological risk, with activation of the Nrf2 oxidative stress pathway dominating across reef sites. The two lines of evidence were complementary: target compounds identify the bays as pollution sources, while bioassays show mixture effects are strongest on the reefs. Hence,targeted chemical analysis alone is insufficient to evaluate ecotoxicological risk. Our multidisciplinary approach provides a framework for prioritizing key chemical indicators and bioassays to monitor coral reef water quality.

pharmacology and toxicology↗
bioRxiv2026

Spatial architecture of complex antibody formats dictates pharmacokinetics via FcRn-recycling

Complex antibody formats are advancing in the biotherapeutic landscape to address the need for multi-specificity, tailored valency, and novel mechanisms of action. However, understanding how non-canonical architectures impact fundamental pharmacokinetic pathways remains a critical challenge. While canonical IgGs experience steric hindrance at the endosomal membrane during FcRn engagement, whether -- and how strongly -- this constraint impacts FcRn-mediated recycling across the expanding diversity of non-canonical antibody architectures has remained unknown. By systematically evaluating a diverse panel of rationally designed antibody geometries utilizing orthogonal in vitro assays we demonstrate that spatial layout profoundly influences FcRn-recycling efficiency; inverting the antibody structure by positioning the Fab-domains to the C-terminus (invertbodies) maximizes recycling, whereas crowding the N-terminus severely impairs it. In contrast, non-specific endocytosis was only modestly and inconsistently affected by Fab number, dependent on the Fv-sequence, but not by the spatial architecture itself. Notably, antibody architecture and affinity-enhancing Fc-FcRn mutations act independently yet cooperatively, ultimately revealing a physiological recycling ceiling. These FcRn-recycling dynamics translate with high fidelity to in vivo clearance (CL) in a humanized FcRn mouse model. Across the antibody panel, architecture drove a near 15-fold variance in CL, an effect that collapsed in FcRn-knockout mice. As proof of concept, we applied the invertbody design to a variant of the marketed antibody golimumab, achieving a three-fold reduction in clearance without compromising potency. These findings reveal the magnitude and predictability with which the antibody architecture governs FcRn-recycling and non-specific CL, establishing a rational, generalizable framework to optimize the pharmacokinetics of biotherapeutics.

pharmacology and toxicology↗