Wenchao Lu

The clinical management of glioblastoma (GBM) is severely hindered by rapid resistance to temozolomide (TMZ). Through viability-based phenotypic screening, we identified the translation termination factor GSPT1 (G1 to S phase transition 1) as a critical vulnerability in GBM cells. Structure−activity relationship optimization of an isoindolinone scaffold, specifically focused on improving metabolic stability, led to the discovery of LG-NE-29, a potent molecular glue degrader. This compound efficiently promotes CRBN-dependent ubiquitination and subsequent proteasomal degradation of GSPT1. LG-NE-29 overcomes the metabolic liabilities of early-generation scaffolds, exhibiting an optimized pharmacokinetic profile highlighted by excellent oral bioavailability (F = 76%). Mechanistically, GSPT1 depletion triggers a profound integrated stress response and intrinsic apoptosis. In U87MG xenograft models, oral administration of LG-NE-29 induced significant tumor regression. Collectively, these findings validate GSPT1 as an actionable therapeutic target in GBM and establish LG-NE-29 as a robust pharmacological tool for further targeted protein degradation research.

Targeted protein degradation via molecular glues represents a powerful modality for modulating “undruggable” proteins. Herein, through proteomic profiling of a CRBN‐binding library and rigorous structure‐activity relationship (SAR) refinement, we report the discovery of dWBP4‐1: a first‐in‐class, highly selective, CRBN‐dependent molecular glue degrader of the spliceosome‐associated scaffold protein WBP4. dWBP4‐1 induces rapid, nanomolar degradation of WBP4 via a canonical G‐loop‐mediated mechanism, exhibiting exceptional proteome‐wide selectivity with negligible transcriptomic or alternative splicing perturbation. Leveraging this highly specific target‐glue interaction, we mapped the minimal WBP4 degron to a 41‐amino‐acid sequence to establish a compact, inducible chemical‐genetic platform termed wTAG. When fused to diverse proteins of interest, wTAG enables robust, monotonic degradation devoid of the hook effect. While the wTAG system is highly versatile, we delineate its boundaries when applied to challenging targets like Cyclin D1, where factors such as steric hindrance, lysine availability, complex sequestration, and tag accessibility (N‐ vs. C‐terminal fusion) must be carefully interrogated. Collectively, this study highlights the discovery of a highly selective WBP4 molecular glue and translates its underlying degron into a robust tool for precise protein control.

Targeted protein degradation via molecular glues represents a powerful modality for modulating “undruggable” proteins. Herein, through proteomic profiling of a CRBN‐binding library and rigorous structure‐activity relationship (SAR) refinement, we report the discovery of dWBP4‐1: a first‐in‐class, highly selective, CRBN‐dependent molecular glue degrader of the spliceosome‐associated scaffold protein WBP4. dWBP4‐1 induces rapid, nanomolar degradation of WBP4 via a canonical G‐loop‐mediated mechanism, exhibiting exceptional proteome‐wide selectivity with negligible transcriptomic or alternative splicing perturbation. Leveraging this highly specific target‐glue interaction, we mapped the minimal WBP4 degron to a 41‐amino‐acid sequence to establish a compact, inducible chemical‐genetic platform termed wTAG. When fused to diverse proteins of interest, wTAG enables robust, monotonic degradation devoid of the hook effect. While the wTAG system is highly versatile, we delineate its boundaries when applied to challenging targets like Cyclin D1, where factors such as steric hindrance, lysine availability, complex sequestration, and tag accessibility (N‐ vs. C‐terminal fusion) must be carefully interrogated. Collectively, this study highlights the discovery of a highly selective WBP4 molecular glue and translates its underlying degron into a robust tool for precise protein control.

Cyclin-dependent kinase 2 (CDK2) represents a critical therapeutic target in tumors resistant to CDK4/6 inhibitors or with CCNE1 amplification. However, selective inhibition of CDK2 remains challenging owing to the high structural homology among CDKs. In this study, we identify B10 and B12 as cereblon (CRBN)-based molecular glue degraders that selectively degrade CDK2. Ternary complex structures reveal a noncanonical recruitment mode centered on CDK2 Glu57, which bypasses the canonical G-loop/β-hairpin and kinase glycine-rich loop interactions and is stabilized by an extended CRBN-CDK2 interface. Mechanistically, these degraders inhibit retinoblastoma (Rb) phosphorylation and induce G1/S-phase arrest, suppressing CDK2-dependent cell proliferation. B12 further exhibits improved pharmacokinetics, measurable oral bioavailability, and in vivo target engagement, achieving intratumoral CDK2 degradation following intraperitoneal administration. Collectively, this study provides a structural blueprint for designing selective kinase degraders and establishes B12 as a chemically tractable probe for targeting CDK2-driven malignancies.

Glutathione S-transferase omega 1 (GSTO1) promotes activation of the NLRP3 inflammasome through deglutathionylation of NEK7, contributing to pro-inflammatory signaling relevant to cancer and inflammatory disease, yet selective and cell-active GSTO1 inhibitors remain limited. Using a live-cell PRM-ABPP platform (ChomiXScreenTM), we identified a covalent small-molecule inhibitor (A1) that engages GSTO1 at Cys32 in intact cells, followed by ligand-based optimization to generate a focused analogue series. Among these, A13 exhibited sustained GSTO1 engagement (kinact/KI = 226 M⁻¹·s⁻¹), high proteome-wide cysteine selectivity as assessed by competitive Ucov-ABPP, and improved metabolic stability in human liver microsomes. High-resolution crystal structures revealed that A13 adopts an unexpected allosteric covalent binding mode distinct from those reported for existing GSTO1 inhibitors. Functionally, covalent targeting of GSTO1 Cys32 significantly suppressed LPS-induced IL-1β and IL-18 secretion in primary human monocyte-derived macrophages. Together, these findings identify a previously unrecognized allosteric covalent binding mode for GSTO1 inhibition and demonstrate the utility of live-cell chemoproteomics for discovering selective, functional covalent inhibitors to modulate inflammation relevant to cancer. Citation Format: Nan Chen, Fengying Zhang, Wenchao Lu. Chemoproteomic discovery of allosteric covalent GSTO1 inhibitors reveals a previously unrecognized binding mode with anti-inflammatory activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB030.

Molecular glue degraders (MGDs) offer a sophisticated, proximity-based approach to protein modulation. In this study, we introduce LJY-3-60, a novel proximity-inducing agent that unexpectedly triggers the potent and selective autodegradation of CRBN. Evidence from CRISPR-Cas9 screening and IP-MS reveals that this degradation process is strictly governed by the intrinsic CRL4 ^CRBN machinery, independent of any extrinsic E3 recruitment. Through a combination of cellular and biophysical characterizations, we demonstrate that LJY-3-60 acts as a molecular bridge to template CRBN homodimerization. This mechanism is unequivocally elucidated by the atomic-resolution co-crystal structure of the CRBN ^Midi -LJY-3-60 complex. The structure explicitly delineates the homodimerization interface, revealing how the ligand reorganizes the protein surface to stabilize a non-canonical architecture that drives trans-autoubiquitination and subsequent proteasomal degradation. Furthermore, LJY-3-60 serves as a highly effective, controllable off-switch to mitigate PROTAC-induced toxicity. Ultimately, this work delivers a robust chemical tool for modulating CRBN stability. By demonstrating how a small molecule can functionally mimic an endogenous E3 substrate’s degron to catalyse targeted autodegradation, this study establishes a rational structural framework for designing the next generation of self-destructive modulators in targeted protein degradation (TPD) therapeutics.

Enzymatically activated prodrugs can enable context-specific target inhibition. AKR1C3 is an NADPH-dependent aldo-ketoreductase involved in androgen metabolism, prostaglandin synthesis, and cell proliferation that is overexpressed in tumors, making it an ideal candidate for tumor-specific prodrug activation. Reported prodrugs that exploit AKR1C3 catalytic activity release DNA-intercalating toxins or other non-selective poisons upon enzymatic activation. OBI-3424, a prodrug of a DNA alkylating agent, is a prominent example of this strategy. To extend this concept to selective enzymatic inhibitors, we have developed AKR1C3-activated prodrugs of OTS964, a CDK11 inhibitor. We have probed the activities of the compounds with biochemical and cellular assays, finding specific activation of the lead prodrug by AKR1C3. Upon enzymatic conversion, the compound recapitulates the cellular activity of the parent compound. These results demonstrate that the AKR1C3-activated prodrug strategy can be used to convert selective kinase inhibitors into context-dependent prodrugs. Extension of this approach may enable synthesis of prodrugs for targeted therapies that spare normal tissue, further improving their therapeutic windows.