Zhang Zhang

Pharmacological invention of RET offers a compelling strategy to treat patients harboring RET fusions or mutations. Selective RET inhibitors, including pralsetinib and selpercatinib, have demonstrated substantial clinical benefits. However, this efficacy is often compromised by the occurrence of resistance, particularly RET solvent front mutations G810C/R. To address this problem, we performed a systematic structure−activity optimization based on our reported RET inhibitors. Our efforts yielded F73, a next generation RET inhibitor with potent activity against RET mutations including V804M and G810C/R. F73 effectively suppressed RET phosphorylation and downstream SHC activation in Ba/Fa3 cells harboring various RET resistance mutations. Furthermore, it induced apoptosis and cell-cycle arrest in a dose-dependent manner in CCDC6-RET and CCDC6-RET-G810R Ba/F3 cells. Notably, F73 exhibited robust antitumor efficacy in Ba/F3-RET-G810R xenograft models, outperforming selpercatinib, thus supporting its potential to overcome resistance mediated by RET gatekeeper (V804M) and solvent-front (G810C/R) mutations.

Threonine tyrosine kinase (TTK), a core component of the spindle assembly checkpoint, plays an essential role in mitosis, and its inhibition has emerged as a promising therapeutic strategy for human cancers. We previously reported multiple approaches to target TTK, including reversible inhibitors, covalent inhibitors, and PROTAC degraders. In this study, we advance these efforts by developing a novel monovalent degrader of TTK. The representative compound, 26, generated by appending an electrophilic monomethyl fumarate handle to a TTK inhibitor, effectively induced TTK degradation and demonstrated superior antiproliferative activity across diverse cancer cell lines. Mechanistic investigations suggested that compound 26 primarily engages RNF126 and stabilizes its association with TTK, thereby inducing TTK ubiquitination and subsequent proteasomal degradation. Collectively, this work provides the first example of a TTK molecular glue-like degrader and introduces a new electrophilic handle for the rational design of degraders with reduced nonspecific cytotoxicity.

Traditional drug discovery faces challenges from fragmented data, tacit knowledge dependence, and inefficient design-test cycles. We present an integrated AI workflow combining multimodal data curation, encoded medicinal chemistry rules, and physics-based simulations to establish a closed-loop from patent analysis to candidate validation. Application across six patents for four targets successfully deciphered SAR and identified representative molecules. A retrospective case study on RET kinase inhibitors demonstrated the workflow’s efficiency: focusing on patent-derived SAR enabled rapid discovery of Cpd-31 (RET IC50 = 0.48 nM, 95.88% tumor inhibition at 10 mg/kg) with only three initial compounds synthesized. This data-centric approach streamlines early drug discovery by providing objective molecular design foundations, significantly reducing synthetic efforts and hypothesis-driven exploration.

Covalent kinase inhibitors (CKIs) serve as potent therapeutics, yet their development largely depends on conserved cysteine residues. Many kinases lack accessible cysteines or develop resistance mutations at these sites, limiting clinical utility. To diversify targetable nucleophilic amino acids, we developed a modular strategy for arginine reactive CKIs using two warhead types: O-cyanobenzaldehyde (CNBA) and phenylglyoxal (PGO). We first synthesized RA2, a CNBA-based AURKA inhibitor targeting arginine (R220), which showed weak cellular activity (GI50 > 2 μM). Using PGO warhead, we generated covalent inhibitors C1 against ALK-G1202R and L1a against TRKA-G595R; both strongly inhibited arginine-mutant kinases but showed unsatisfactory cellular potency. Further optimization of PGO electrophilicity via methoxy substitution yielded L1c, which exhibited potent cellular activity (GI50 = 0.39 μM) against drug-resistant Ba/F3-CD74-TRKA-G595R cells and sustained target engagement. Collectively, this work expands the CKI toolbox to include arginine-targeting warheads and provides a modular framework to overcome point mutation-driven resistance.

Targeted protein degradation (TPD) is a promising therapeutic strategy, yet its application remains constrained by the limited repertoire of available E3 ubiquitin ligases, primarily CRBN and VHL. Here, we identify RNF213 as a recruitable E3 ligase that mediates protein degradation induced by molecular glue degraders. We developed CYB-5067 by equipping the pan-FGFR inhibitor Infigratinib with a minimal dibromoacetamide covalent warhead. This covalent molecular glue recruits RNF213 to potently degrade FGFR1-4, with the strongest effect on FGFR2 (DC₅₀ = 27 nM, D_max = 96%). CYB-5067 outperforms parent inhibitors in vitro (IC₅₀ = 3.8 nM) and shows comparable antitumor efficacy in vivo (TGI = 94.6%), with sustained target suppression and no apparent hook effects under the tested conditions. Notably, the dibromoacetamide warhead is transplantable, enabling selective degradation of other challenging targets such as WEE1 and CDK12, which regulate cell-cycle progression and transcription. This offers a rational strategy for creating molecular glues. Our work identifies RNF213 as an exploitable ligase for TPD and establishes covalent molecular glues as a modular platform. This strategy expands the scope of degrader design beyond conventional E3 ligases, offering an avenue for developing potent and selective therapeutics.

We herein report a highly diastereo- and enantioselective palladium-catalyzed dynamic kinetic desymmetrization of heterobicyclic alkenes with heterobiaryl sulfonates. This methodology enables the streamlined construction of complex heterobiaryl atropisomers featuring both an axis of chirality and two contiguous stereocenters. Comprehensive mechanistic investigations, synergistically supported by DFT calculations, firmly establish a dynamic kinetic asymmetric transformation (DYKAT) pathway. Furthermore, the profound utility of these structurally privileged scaffolds is underscored by versatile late-stage diversification, alongside their promising applications as novel chiral organocatalysts and potent antitumor lead candidates.

Shikonin is a natural naphthoquinone with anticancer activity; however, its therapeutic potential is limited by modest potency and suboptimal drug-like properties. To address these limitations, we designed and synthesized 31 shikonin derivatives through a medicinal chemistry hybridization strategy that retained the redox-active naphthoquinone core while introducing privileged structural motifs frequently associated with enhanced biomolecular interactions and cellular activity. Structure–activity relationship analysis identified compound 3k as a lead, exhibiting approximately 10-fold greater antiproliferative potency than shikonin, with preferential sensitivity observed in gastric cancer cell lines relative to other tested cancer types and normal gastric epithelial cells. The anticancer activity of 3k was further validated in a gastric cancer xenograft model in vivo. Proteomic profiling and mechanistic studies revealed activation of the integrated stress response (ISR) and reactive oxygen species (ROS) pathways, which were also enriched in gastric cancer data sets, leading to the induction of both apoptosis and ferroptosis. Collectively, these findings establish a structure-dependent optimization of shikonin-derived naphthoquinones and identify 3k as a promising lead compound for further development of redox-active anticancer agents.

The efficacy of FLT3 inhibitors in acute myeloid leukemia (AML) is severely limited by resistance mutations, particularly the recalcitrant gatekeeper F691L and activation loop D835V/Y variants. Herein, through the structure-guided optimization of our previously reported lead SILA-123, we identified FYJ-195, a highly potent type II FLT3 inhibitor capable of overcoming these recalcitrant mutants. FYJ-195 exhibited single-digit nanomolar potency against Ba/F3-FLT3-ITD-F691L (IC₅₀ = 9.09 nM) and subnanomolar activity against Ba/F3-FLT3-ITD-D835Y (IC₅₀ = 4.64 nM) and Ba/F3-FLT3-ITD-D835V (IC₅₀ = 0.76 nM). In vivo, FYJ-195 induced profound tumor regression (TGI = 125%) in the MV4-11 xenograft model (10 mg/kg) and achieved robust tumor growth suppression (TGI = 68.6%) in the Ba/F3-FLT3-ITD-F691L model (50 mg/kg), where quizartinib was ineffective. Mechanistic studies confirmed that FYJ-195 effectively blocked FLT3 signaling and induced apoptosis without observable toxicity. Collectively, FYJ-195 represents a promising lead candidate for drug-resistant AML.

Accurate prediction of drug‐target interactions constitutes a crucial foundation for drug discovery. DualPG‐DTA is presented, a general framework for binding affinity prediction that integrates two pre‐trained language models to generate atomic‐level molecular representations and residue‐level protein embeddings. The architecture constructs dual molecular‐protein graphs processed through dedicated graph neural networks equipped with dynamic attention mechanisms to extract context‐aware sequence‐level features, which are fused via a multimodal module for affinity predictions. Benchmark results show that DualPG‐DTA consistently outperforms existing models across all metrics. Applied to CDK9 inhibitor discovery, the framework is used to develop robust regression/classification models and identified compound C1 as a novel CDK9 inhibitor with an IC ₅₀ of 1.2 nM. C1 demonstrates exceptional CDK family selectivity alongside optimal pharmacokinetic properties, including prolonged half‐life, adequate clearance, robust plasma exposure, and oral bioavailability. Notably, oral C1 demonstrated potent antitumor efficacy in a Venetoclax‐resistant MV4‐11 acute myeloid leukemia (AML) xenograft model, with concurrent demonstration of favorable tolerability and safety profiles. Collectively, the study not only establishes a unified framework for precise binding affinity prediction but also identifies C1 as a highly promising therapeutic lead targeting CDK9 to conquer Venetoclax resistance in AML.

SARS-CoV-2 virus contains two highly conserved domains, the papain-like protease (PLpro) and main protease (Mpro), which play important roles in virus replication, immune suppression, and the induction of inflammation in host tissue. In this study, we applied small-molecule chip screening, enzymatic assays, SARS-CoV-2 spike pseudotyped virus detection and molecular docking to find potential Mpro or PLpro inhibitors. Two small molecules, oxytocin and risedronate sodium, stood out in drug repurposing. Oxytocin and risedronate sodium were shown to influence the activities of Mpro and PLpro, thereby preventing the virus from replication, which may alleviate SARS-CoV-2 infection. Thus, oxytocin, risedronate sodium, and cephalosporins may expand the drug library for treating coronavirus infection.