EvoBind-multimer is presented, a deep learning framework for the de novo design of molecular glues directly from protein sequences that generates small macrocyclic peptides that bridge user-defined protein pairs without requiring prior interface knowledge or existing ligands.
Abstract
The engineering of induced proximity has transformed drug discovery, yet the development of molecular glues remains largely serendipitous and restricted to the retrospective optimisation of accidental discoveries. Here, we present EvoBind-multimer, a deep learning framework for the de novo design of molecular glues directly from protein sequences. Unlike structure-based docking, our method generates small macrocyclic peptides that bridge user-defined protein pairs without requiring prior interface knowledge or existing ligands. We applied this framework to recruit the E3 ligase VHL to two challenging oncoproteins: KRAS and BRD4. Live-cell NanoBRET demonstrated robust design-induced proximity for both pairs. Mechanistic validation demonstrated that the generated macrocycles form functional VHL-target ternary complexes capable of driving Cullin-RING ligase-dependent proteasomal degradation and downstream signalling shutdown. Finally, evaluation in patient-derived xenograft neuroblastoma tumoroids revealed that ternary complex processing is deeply context-dependent: identical macrocycles acted as potent degraders in one patient model, yet functioned as stabilising “LOCKTACs” in another, driving VHL-dependent target sequestration without turnover. By enabling the de novo design of induced proximity from sequence alone, EvoBind-multimer provides a route towards designing new protein functions.
Molecular glue degraders are an emerging class of small molecule allosteric modulators that induce or stabilize protein-protein interactions, enabling targeted degradation of previously intractable proteins. By redirecting E3 ligases to recognize neosubstrates, proteins that are not typically recognized by a specific E3 ubiquitin ligase, they expand the scope of drug discovery beyond traditional paradigms. We review mechanistic principles underlying molecular glue activity, including cooperativity, weak affinity interactions, structural degrons, and higher-order complex formation. We discuss discovery strategies, from serendipitous identification to emerging rational and chemoproteomic approaches, and key E3 ligase systems with relevance to oncology. We highlight clinical and preclinical applications, alongside challenges such as resistance mechanisms, context-dependent activity, and limitations in predicting neosubstrates. Molecular glues are transitioning from serendipitous discoveries to a mechanism-driven therapeutic platform. Progress depends on integrating structural biology, proteomics, and computational modeling to enable rational design and improve predictability. Expanding the repertoire of E3 ligases and understanding context-specific degradation will be critical to fully realize their potential in oncology and beyond.
E. Ozdemir, Hyunbum Jang, Ozlem Keskin et al.· Medicinal research reviews (...· 0 citations
Small molecules that induce protein interactions hold tremendous potential as new medicines, as probes for molecular pathways, and as tools for agriculture. Explosive growth of targeted protein degradation drug development has spurred renewed interest in proximity inducing molecules and especially molecular glue degraders. These compounds catalyze destruction of disease-causing proteins by reshaping protein surfaces and promoting cooperative binding between ubiquitylating enzymes and target proteins. Molecular glue discovery for pre-defined targets is a major challenge in contemporary drug discovery. Here I will discuss how we address these important chemical challenges through molecular glue discovery enabled by targeted degron display. By leveraging mechanisms such as electrophilic covalent bonding, electrostatic interactions, or cation-pi interactions, I have identified a range of potent molecular glue degraders that recruit previously unligandable ubiquitylating factors for multiple therapeutically relevant epigenetic regulators and kinases. This "chemocentric" approach provides a powerful strategy to discover molecular glues that induce proximity to ubiquitin ligases with similarly desirable properties.
Zhe Zhuang. Molecular glue discovery enabled by targeted degron display [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr A054.
Natural cyclic peptides have long served as a rich reservoir of bioactivity, occupying a unique region of the drug space that bridges the gap between small molecules and large biologics, and researchers are rationally engineering next-generation macrocycles, positioning them at the frontier of modern drug development.
Greta Bergamaschi, Giulia Lodigiani, Stefano Gandolfi et al.· Current Opinion in Chemical...· 0 citations
These results establish motif scaffolding of surface-complementing seeds as an effective strategy for overcoming current limitations of de novo generative models, enabling the design of proteins that can engage challenging interface sites.
D. Britton, Dia A. Ghose, J. Halpin et al.· bioRxiv· 0 citations
LinkerBridge is proposed, an equivariant framework that unifies biochemical semantics with physical constraints through two innovations: a Contextual Interaction-Aware Representation module that internalizes pre-existing bio-chemical semantics and a Differentiable Physical Guidance mechanism derived from Van der Waals potentials to steer generation away from collision zones.
Mengwei Sun, Chengwei Ai, Xiaoyi Liu et al.· 0 citations
Molecular glue degraders (MGDs) reprogram E3 ligases to eliminate neosubstrates, yet their application has largely been confined to CRBN. Here, we identify caspase-2 as a new neosubstrate for von Hippel-Lindau (VHL), expanding the scope of VHL-based MGDs. Guided by a focused VHL ligand library design, we employed TurboID-based proximity labeling to discover stereoisomeric compounds (dCASP2-1 and dCASP2-2) that selectively recruit caspase-2 to VHL and promote its ubiquitin-proteasome system-dependent degradation. Further structure-activity relationship (SAR) studies yielded dCASP2-3 and dCASP2-4, which enhanced degradation potency (by 622-fold relative to dCASP2-1) and abolished enantioselectivity. Mechanistic mapping localized the degrader-induced interface to a two-helix region of the caspase-2 CARD domain, with residues H33, P34, and D100 essential for VHL engagement. Degron-guided computational modeling of the VHL/MGD/caspase-2 ternary complex provided structural insight into neosubstrate recognition. Together, we report the development of VHL molecular glues that selectively and potently degrade caspase-2, offering chemical probes to interrogate its functions in apoptosis and stress responses, while broadening the substrate landscape of VHL-based MGDs.
Jian-Zhong Hu, Weixian Deng, Shu-Ching Ou et al.· bioRxiv· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
