Yang Wang

Diabetes mellitus results from inadequate pancreatic β-cell mass or function, whereas mature β-cells are generally incapable of spontaneous proliferation. Therefore, promoting β-cell proliferation could be an approach toward diabetes interventions. Over the past decades, dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) has emerged as a key negative regulator of β-cell proliferation via modulating the NFAT signaling pathway and DREAM complex assembly, thereby establishing DYRK1A as a promising therapeutic target for diabetes. In this minireview, we provide an overview of recent progress (2018-2025) in medicinal chemistry toward small-molecule DYRK1A inhibitors for β-cell regeneration. Particular attention is paid to scaffold design, Structure-activity Relationship (SAR) analysis, and structure-based optimization of representative compounds. We systematically discuss the structural modifications and biological evaluation of natural product-derived scaffolds (such as β-carboline harmine and its analogues, xanthone desmethylbellidifolin) and synthetic scaffolds (including aminopyrazine, 6-azaindole, 1,5- naphthyridine and 1,3,4-thiadiazine), as well as their proliferative effects on human β-cells in vitro and in vivo. Additionally, we highlight medicinal chemistry strategies aimed at improving DYRK1A selectivity, reducing off-target effects, and uncoupling pro-proliferative activity from cytotoxicity. Finally, this review outlines the current challenges and future prospects for the rational design of potent, selective, and β-cell-targeted DYRK1A inhibitors from a medicinal chemistry perspective.

Telomerase, responsible for extending telomeres and maintaining the malignant potential of tumors, has long been deemed a promising anticancer target. Nonetheless, because of its complex composition, the discovery of highly efficient telomerase inhibitors is a challenging task. Herein, we identify the blockage of telomerase assembly via targeting TCAB1 as a novel avenue for potent telomerase inhibition. Upon this strategy, (R)-(3,4-dimethoxyphenyl)(3-(3-hydroxypyrrolidin-1-yl)phenyl)methanone (R)-1b (IC50 = 2.04 nM), which directly targets TCAB1 and impairs telomerase assembly via obstructing the TCAB1-hTR interaction, has been discovered. Notably, its binding pocket and the critical residues are confirmed for further drug design. In vivo, (R)-1b remarkably sensitized tumors to small-molecule PD-L1 inhibitors and induced tumor regression, underscoring its potential for augmenting the efficacy of tumor immunotherapy. This study paves the way for the exploration of telomerase inhibitors with a distinctive mechanism of action via targeting TCAB1 and blocking telomerase assembly.

Targeting the 'undruggable' MYC oncogene remains a challenging objective. Despite substantial research efforts, a majority of MYC direct inhibitors discovered so far lack in vivo efficacy. Herein, benzofuranyl-pyrazole has been identified as a structurally novel scaffold directly disrupting MYC function. Among the final compounds, 15 displayed 10-fold enhanced antiproliferative activity over MYCi975, a well-established MYC inhibitor, against PC-3 cells. Besides, it exhibited low micromolar to submicromolar activities against 14 other neoplastic cell lines. Its direct perturbation of MYC function was confirmed by the obstruction of MYC/MAX interaction in Co-IP and AlphaLISA assays. Moreover, it decreased MYC thermal stability, triggered MYC degradation, and impaired expression of MYC-responsive luciferase. Notably, 15 potently delayed tumor growth and outperformed MYCi975 in a mouse allograft model, even when administered every other day. Meanwhile, it synergized with a small-molecule immune checkpoint inhibitor in vivo, highlighting its potential application in immunotherapy.

The vast majority of tumor cells maintain the length of the telomeres through a telomerase-dependent maintenance mechanism, allowing for unlimited proliferation. TCAB1 is indispensable for the correct assembly of telomerase complexes and the delivery of telomerase to the telomere. Therefore, this study aimed to explore small molecules capable of interfering with the assembly of TCAB1 and the telomerase complex as novel efficient telomerase inhibitors. Through virtual screening, biological evaluation, and the confirmation of target engagement, the potential ligands of TCAB1 effectively inhibiting telomerase activity were discovered. Among them, compound 9 exhibited telomerase inhibitory activity at a two-digit nanomolar level (IC₅₀ = 0.03 μM), which was dramatically enhanced in comparison with the previously reported telomerase inhibitors. This research, based on the blockage of telomerase assembly through disturbing TCAB1, provides a novel strategy and a potential target for telomerase inhibitor discovery.

Despite being a highly sought-after therapeutic target for human malignancies, myelocytomatosis viral oncogene homologue (MYC) has been considered intractable due to its intrinsically disordered nature, making the discovery of in vivo effective inhibitors that directly block its function challenging. Herein, we report structurally novel alkynyl-substituted phenylpyrazole derivatives directly perturbing MYC function. Among them, compound 37 exhibited superior antiproliferative activities to those of MYCi975 against multiple malignant cell lines. It induced dose-dependent MYC degradation in cells with degradation observed at the concentration as low as 1.0 μM. Meanwhile, its direct suppression of MYC function was confirmed by the capability to inhibit the binding of MYC/MYC-associated protein X (MAX) heterodimer to DNA consensus sequence, induce MYC thermal instability, and disturb MYC/MAX interaction. Moreover, 37 demonstrated enhanced therapeutic efficacy over MYCi975 in a mouse allograft model of prostate cancer. Overall, 37 deserves further development for exploring MYC-targeting cancer therapeutics.