Ubiquitin carboxyl-terminal hydrolase 1 (USP1) is a synthetic lethality target in cancers with high replication stress, such as tumors with BRCA gene mutations or homologous recombination deficiency (HRD). Targeting USP1 has emerged as a promising approach to overcome resistance observed in BRCA/HRD-driven tumors. Aigen Sciences Inc. developed and presented data for AIG-07025, a potent and selective USP1 inhibitor.
Werner syndrome helicase (WRN), belonging to the RecQ helicase family, represents a synthetic lethal vulnerability in MSI-H cancers, providing a strong rationale for therapeutic inhibition. Researchers from Simcere Zaiming Pharmaceutical Co. Ltd. reported the discovery and preclinical characterization of ZMS-4084, a novel WRN inhibitor.
Researchers from Sunshine Biopharma Inc. and the University of Arizona reported the discovery and preclinical characterization of MR-1-114, a noncovalent inhibitor of the SARS-CoV-2 papain-like protease (PLpro).
Syracuse University recently presented a comprehensive preclinical program describing the rational design and optimization of peptide antagonists targeting the GDF15/GFRAL/RET receptor complex to mitigate nausea, emesis, anorexia and wasting associated with chemotherapy-induced stress signaling.
Mixed lineage kinase domain-like pseudokinase (MLKL), a key effector of necroptosis, is highly expressed in hepatocellular carcinoma (HCC), and its targeting may promote parthanatos-mediated immunogenic cell death. Researchers from the Chinese Academy of Sciences and collaborators described the discovery and preclinical characterization of C-116, a MLKL PROTAC degrader developed using AI-assisted rational drug discovery.
Cisplatin is widely used in chemotherapy regimens for many solid tumors, yet its therapeutic benefit is counterbalanced by significant toxicity and immunologically related limitations. Researchers from Jiangxi University of Chinese Medicine described the preclinical efficacy of the PD-L1-targeted cisplatin prodrug MN42-81, designed to overcome these limitations.
Signal transducer and activator of transcription 3 (STAT3) is a central mediator of cytokine and growth factor signaling and is aberrantly activated in approximately 70% of human cancers. Persistent STAT3 signaling drives tumor proliferation, survival, metastasis, angiogenesis, immune evasion and inflammation. Researchers from the University of Michigan reported the discovery and preclinical characterization of SD-965, a selective STAT3 PROTAC degrader.
Microtubule-associated serine/threonine kinase-like protein (MASTL) is a key regulator of mitotic progression and cell-cycle control. Researchers from the Korea Institute of Radiological and Medical Sciences reported the preclinical efficacy of MKI-3, a selective MASTL inhibitor.
Caspase-2-mediated cleavage of tau at Asp314 generates a neurotoxic fragment, Δtau314, that drives early synaptic dysfunction in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). This fragment accumulates at synapses, disrupts glutamatergic signaling and contributes to cognitive impairment in vivo.
Retinoid X receptor γ (RXRγ) is a key nuclear receptor that sustains androgen receptor (AR) signaling. In castration-resistant prostate cancer (CRPC), RXRγ contributes to disease progression by maintaining adaptive transcriptional networks that promote therapy resistance and tumor cell survival.
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