Motivation: Dipeptidyl peptidase IV (DPP‐IV) is a key therapeutic target for type 2 diabetes, and its inhibitory peptides are a promising class of therapeutic agents. However, the discovery of these promising drugs has been restricted, as many existing computational predictors are based on datasets that have remained static for several years. Results: Here, we first presented a newly curated and expanded benchmark dataset, then introduced Bilingua‐DPP‐IV, a bimodal deep learning framework that integrates features from both amino acid sequences and molecular structures. Our approach leveraged embeddings from the large‐scale pretrained models ESM C and Uni‐Mol2, processed through a convolutional neural network with an optimized gated fusion mechanism. On an independent test set, the Bilingua‐DPP‐IV ensemble model achieved a Matthews correlation coefficient of 0.764 and an area under the receiver operating characteristic curve of 0.963. On an external validation set, the model also demonstrated an accuracy of 0.898, exceeding the performance of existing state‐of‐the‐art predictors, such as StructuralDPPIV.
Two advances have reshaped our understanding of α‐synuclein (αSyn) in Parkinson's disease (PD). First, αSyn can assemble through liquid–liquid phase separation (LLPS) and related condensation pathways, forming condensates that mature into Lewy‐body‐like assemblies. Although conventional crowding‐driven LLPS requires supraphysiological protein concentrations, membrane‐templated surface condensation has been reported in vitro at ~10 nM, making this pathway plausible in the lipid‐rich, electrically active enteric nervous system (ENS). Second, seeding‐competent αSyn is detectable in blood before motor onset using seed‐amplification assays. This review asks whether condensate‐derived αSyn generated in the gut constitutes a blood‐borne seed population that is systematically underrepresented by fibril‐biased assays. We evaluate each step of the proposed pathway, including gut‐specific LLPS triggers, release into and survival within the circulation, blood–brain barrier (BBB) traversal, and clinical detection, while distinguishing established evidence from indirect inference and testable hypotheses. Many of these questions are now experimentally accessible. Molecular rotors detect condensates through microviscosity rather than cross‐β structure, condensate‐stage modulators have emerged, and receptor‐interception strategies such as bemcentinib provide opportunities for mechanistic interrogation. Together, these advances position chemical biology to determine whether condensate‐derived seeds contribute to PD pathogenesis.
Breast cancer remains a leading cause of cancer‐related mortality worldwide, highlighting the need for novel therapeutic agents with improved selectivity and multifunctional activity. In this study, a novel cobalt(III) complex, Co(L2) 3 [L2 = 2‐chloro‐N‐(2,2‐dimethyloxazolidine‐3‐carbonothioyl)benzamide], was synthesized and evaluated using integrated in vitro and in silico approaches. The ligand and complex were characterized by FT‐IR, UV–Vis, and 1 H NMR spectroscopy. The antiproliferative activity was assessed in MCF‐7, MDA‐MB‐231, and HUVEC cells using the MTT assay. IC 50 values were 176.95 ± 2.84 µg/mL for MCF‐7, 187.01 ± 0.47 µg/mL for MDA‐MB‐231, and 354.96 ± 1.14 µg/mL for HUVEC cells, corresponding to selectivity indices of 2.01 and 1.90, respectively. Co(L2) 3 reduced colony formation and cell migration and increased glutathione reductase activity. Gene expression analysis showed upregulation of CASP3 and CASP9 and downregulation of BCL2, CDC25A, MMP2, and MMP9, indicating modulation of apoptosis‐, cell‐cycle‐, and metastasis‐related responses. Molecular docking predicted favorable interactions with CDC25A, MMP‐2, and MMP‐9. Collectively, these findings indicate that Co(L2) 3 exhibits preferential in vitro anticancer activity against the tested breast cancer cell lines and warrant further investigation as a potential multifunctional anticancer agent.
Riluzole‐derived benzo[d]thiazoles were investigated as metabolite‐inspired CK1 δ inhibitors, a kinase involved in TDP‐43 phosphorylation and therefore relevant to amyotrophic lateral sclerosis (ALS). Starting from the known CK1 δ activity of riluzole, we examined whether its major hydroxylamine metabolite could preserve target recognition and provide a rational entry point for scaffold optimisation. The metabolite retained CK1 δ inhibition, but its limited chemical stability and toxicity in neuronal cells identified the hydroxylamine group as a critical liability. Replacement of this functionality with a hydrazine converted the fragile metabolite‐derived structure into a more potent and tractable CK1 δ inhibitor series. Structure–activity relationship studies revealed that the hydrazine moiety accommodates broader substitution than the hydroxylamine counterparts, with branched alkyl and benzyl groups giving the most balanced profiles. Docking and molecular dynamics suggested that the improvement could be attributed to an additional hydrogen‐bond with Gly86 in the hinge region. The best derivative combined submicromolar CK1 δ inhibition with passive blood–brain barrier permeability, short‐term cellular tolerance, ATP competitive inhibition, direct target engagement, and preliminary selectivity over GSK3β. Although this compound did not result neuroprotective in an oxidative stress model, it paves the way for a focused benzo[d]thiazole platform for probing CK1 δ biology in ALS.
The development of lysine acetyltransferase (KAT) inhibitors as anticancer agents has progressed rapidly from initial tool compounds to numerous molecules entering clinical trials. The most clinically advanced KAT6A inhibitor, prifetrastat (PF‐07248144), entered Phase III clinical trials in 2025. The discovery of prifetrastat is an excellent example of instrumental contributions made by Australian biomedical and medicinal chemistry researchers to the creation of innovative and cutting‐edge anticancer therapeutics. Within this perspective we summarize KAT6A structural biology and structure–activity relationships (SAR) for acylsulfonylhydrazides, [1,2,4]thiadiazines and benzisoxazole sulfonamide inhibitors in addition to providing updates on KAT6A inhibitors that have already entered into clinical trials. Key clinical challenges and opportunities facing the field are discussed herein.
