Messenger RNA (mRNA) has emerged as a transformative technology for combating viral pandemics and malignancies, with lipid nanoparticle (LNP)-based mRNA vaccines playing a pivotal role in the COVID-19 pandemic. However, current LNP face challenges such as low endosomal escape efficiency (<5%), leading to cargo waste and increased costs. To address this, pHLIP-incorporated LNP (mRNA@LNP-pHLIP), leveraging the pH-dependent membrane-insertion properties of pHLIP is developed to enhance endosomal escape. pHLIP undergoes a conformational change in acidic environments, enabling it to insert into endosomal membranes and promote the release of mRNA into the cytosol. In vitro studies demonstrate a three to fivefold increase in mRNA expression across multiple cell lines, while in vivo experiments show sustained and higher protein expression in mice. Applied to a monkeypox vaccine encoding A35R and M1R antigens, mRNA@LNP-pHLIP elicited stronger immune responses, highlighting its potential for next-generation mRNA therapeutics and vaccines.

Caixia Liu et al. Adv Healthc Mater. 2025.

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Aberrant metabolism of cancer cells is well appreciated, but the identification of cancer subsets with specific metabolic vulnerabilities remains challenging. We conducted a chemical biology screen and identified a subset of neuroendocrine tumors displaying a striking pattern of sensitivity to inhibition of the cholesterol biosynthetic pathway enzyme squalene epoxidase (SQLE). Using a variety of orthogonal approaches, we demonstrate that sensitivity to SQLE inhibition results not from cholesterol biosynthesis pathway inhibition, but rather surprisingly from the specific and toxic accumulation of the SQLE substrate, squalene. These findings highlight SQLE as a potential therapeutic target in a subset of neuroendocrine tumors, particularly small cell lung cancers.

Mahoney CE, Pirman D, Crompton JG, et al. A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition. Nat Commun. 2019;10(1):96.

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Acid ceramidase (aCDase) is an essential enzyme in sphingolipid metabolism and has been linked to various pathological conditions, including cancer and fibrosis. In our previous studies, we observed that inhibiting aCDase with B13 (4 ) helped alleviate liver fibrosis in mouse models and in ex vivo human precision-cut liver slices. However, B13 ( 4 ) showed limited potency, prompting us to search for more effective aCDase inhibitors. During our exploration of well-established urea-type inhibitors, we discovered that the aryl imidazolyl urea scaffold demonstrated both high potency and chemical stability. Among the tested compounds, compound 43 stood out with its nanomolar IC 50 activity against aCDase and its ability to significantly reduce fibrosis markers, such as collagen production, in hepatic stellate cells. Kinetic studies were also performed to understand the interaction of compound 43 with aCDase. Additionally, proteomics analysis of activated hepatic stellate cells treated with compound 43 revealed a notable change in several cellular proteins, including those related to growth factors, such as platelet-derived growth factor receptor (PDGFR). These results indicate that the aryl imidazolyl urea scaffold holds strong potential for further development as a therapeutic option for fibrotic diseases.

Beresis R, et al. ACS Omega. 2025 Jul 31;10(31):34747-34761. doi: 10.1021/acsomega.5c03734. eCollection 2025 Aug 12.

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Messenger RNA (mRNA) therapy has revolutionized modern medicine through its rapid development capabilities and ability to induce effective immune responses, becoming a powerful weapon against infectious diseases. The expression level of target proteins from mRNA sequences is primarily influenced by translational efficiency and stability, which can be significantly enhanced by modifying the 5′ and 3′ untranslated regions (UTRs), codon adaptation index, GC content, and secondary structure. To address the challenges of optimizing mRNA design, we have developed mRNAdesigner, a web server specifically designed to improve mRNA stability and translational efficiency in eukaryotes. Users can input a coding sequence (CDS) along with optional 5′ UTR and 3′ UTR, and the tool optimizes the CDS by reducing unpaired regions, minimizing complex stem-loop structures, and mitigating the use of rare codons while adhering to user-defined GC content preferences. Additionally, mRNAdesigner identifies optimal UTR sequences to enhance translation efficiency and stability. As an open-access computational resource, mRNAdesigner supports full-length mRNA design, enabling researchers to generate high-expression mRNA sequences for efficient protein production in eukaryotic expression systems, providing extra support for vaccine development and protein therapeutics. This is the first such tool that was made open accessible to the public.

Ouyang Mo et al. Nucleic Acids Res. 2025 Jul 7;53(W1):W415-W426. doi: 10.1093/nar/gkaf410.

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Acute myeloid leukemia (AML) is a relapsing and drug-resistant hematologic malignancy. We report AB138, a novel molecular glue degrader that recruits G1-to-S phase transition protein 1 (GSPT1) to cereblon (CRBN). In AML cell lines, AB138 induces rapid, sustained GSPT1 degradation. qPCR and immunoblotting revealed activation of the integrated stress response, as evidenced by eIF2α phosphorylation and the upregulation of ATF3 and CHOP. The subsequent depletion of the oncoproteins MCL1 and c-Myc coincides with the accumulation of cleaved caspase-3 and cleaved PARP and marked apoptosis. Flow cytometric analysis confirmed pronounced S-phase arrest together with an increase in the number of Annexin V-positive cells. Oral administration of AB138 significantly reduces the tumor burden in an MV-4-11-Luc xenograft model without overt toxicity. These findings demonstrate that efficient GSPT1 degradation by AB138 promtoes integrated stress signaling and downregulates the survival-promoting BCL-2 family member MCL1 and the oncogenic driver c-Myc, leading to potent antileukemic activity in vitro and in vivo and supporting further development of AB138 for AML therapy.

Liqiang Wang, Xin Cai, Yongsheng Wang, Yang Kong, Qingchun Wu, Wei Hu, et al. Invest New Drugs. 2025 Jun;43(3):646-655. doi: 10.1007/s10637-025-01541-8. Epub 2025 May 14.

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One of the hallmarks of cancer is high levels of DNA replication stress and defects in the DNA damage response (DDR) pathways, which are critical for maintaining genomic integrity. Ataxia telangiectasia and Rad3-related protein (ATR) is a key regulator of the DDR machinery and an attractive therapeutic target, with multiple ATR inhibitors holding significant promise in ongoing clinical studies. Herein, we describe the discovery and characterization of ART0380 (6 ), a potent and selective ATR inhibitor with a compelling in vitro and in vivo pharmacological profile currently undergoing Phase 2 clinical studies in patients with advanced or metastatic solid tumors as monotherapy and in combination with DNA-damaging agents ( NCT04657068 and NCT05798611 ). ART0380 ( 6) has a favorable human PK profile suitable for both intermittent and continuous once-daily (QD) dosing, characterized by a dose-proportional increase in exposure and low variability.

Carroll CL, Li M, Wu Q, et al. J Med Chem. 2024 Dec 26;67(24):21890-21904. doi: 10.1021/acs.jmedchem.4c01595. Epub 2024 Dec 4.

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Background: Tau post-translational modifications (PTMs) result in the gradual build-up of abnormal tau and neuronal degeneration in tauopathies, encompassing variants of frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD). Tau proteolytically cleaved by active caspases, including caspase-6, may be neurotoxic and prone to self-aggregation. Also, our recent findings show that caspase-6 truncated tau represents a frequent and understudied aspect of tau pathology in AD in addition to phospho-tau pathology. In AD and Pick’s disease, a large percentage of caspase-6 associated cleaved-tau positive neurons lack phospho-tau, suggesting that many vulnerable neurons to tau pathology go undetected when using conventional phospho-tau antibodies and possibly will not respond to phospho-tau based therapies. Therefore, therapeutic strategies against caspase cleaved-tau pathology could be necessary to modulate the extent of tau abnormalities in AD and other tauopathies. Methods: To understand the timing and progression of caspase activation, tau cleavage, and neuronal death, we created two mAbs targeting caspase-6 tau cleavage sites and probed postmortem brain tissue from an individual with FTLD due to the V337M MAPT mutation. We then assessed tau cleavage and apoptotic stress response in cortical neurons derived from induced pluripotent stem cells (iPSCs) carrying the FTD-related V337M MAPT mutation. Finally, we evaluated the neuroprotective effects of caspase inhibitors in these iPSC-derived neurons. Results: FTLD V337M MAPT postmortem brain showed positivity for both cleaved tau mAbs and active caspase-6. Relative to isogenic wild-type MAPT controls, V337M MAPT neurons cultured for 3 months post-differentiation showed a time-dependent increase in pathogenic tau in the form of caspase-cleaved tau, phospho-tau, and higher levels of tau oligomers. Accumulation of toxic tau species in V337M MAPT neurons was correlated with increased vulnerability to pro-apoptotic stress. Notably, this mutation-associated cell death was pharmacologically rescued by the inhibition of effector caspases. Conclusions: Our results suggest an upstream, time-dependent accumulation of caspase-6 cleaved tau in V337M MAPT neurons promoting neurotoxicity. These processes can be reversed by caspase inhibition. These results underscore the potential of developing caspase-6 inhibitors as therapeutic agents for FTLD and other tauopathies. Additionally, they highlight the promise of using caspase-cleaved tau as biomarkers for these conditions. Keywords: Active caspase-6; FTLD; Neoepitope antibody; Postmortem; Tau cleavage; Tauopathies; V337M MAPT mutation; iPSCs.

Theofilas P, et al. Mol Cell Neurosci. 2024 Sep:130:103954.

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Purpose: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed. Experimental design: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models. To refine ATM LOF as a predictive biomarker, we performed a comprehensive pan-cancer analysis of ATM variants in patient tumors and then assessed the ATM variant-to-protein relationship. Finally, we assessed a novel ATM LOF biomarker approach in retrospective clinical data sets of patients treated with platinum-based chemotherapy or ATR inhibition. Results: ART0380 had potent, selective antitumor activity in a range of preclinical cancer models with differing degrees of ATM LOF. Pan-cancer analysis identified 10,609 ATM variants in 8,587 patient tumors. Cancer lineage-specific differences were seen in the prevalence of deleterious (Tier 1) versus unknown/benign (Tier 2) variants, selective pressure for loss of heterozygosity, and concordance between a deleterious variant and ATM loss of protein (LOP). A novel ATM LOF biomarker approach that accounts for variant classification, relationship to ATM LOP, and tissue-specific penetrance significantly enriched for patients who benefited from platinum-based chemotherapy or ATR inhibition. Conclusions: These data help to better define ATM LOF across tumor types in order to optimize patient selection and improve molecularly targeted therapeutic approaches for patients with ATM LOF cancers.

Pilié PG, Hung Le et al. Clin Cancer Res. 2024 May 15;30(10):2121-2139. doi: 10.1158/1078-0432.CCR-23-1763.

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