Hsing-Pang Hsieh

The first asymmetric total synthesis of Lycopodium alkaloids bearing a 1,2-amino alcohol motif, including (-)-palhinine B, (-)-palhinine C, and (+)-palhinine B, has been achieved. The synthesis features early stage installation of a chiral C2-OH group from a tyrosine-derived 1,2-amino alcohol, which governs the overall stereochemical outcome at C7, C13, C15, and a quaternary stereogenic center at C12 of the tetracyclic palhinine skeleton. A highly diastereoselective Diels-Alder reaction of a masked ortho-benzoquinone, followed by a thiol-mediated acyl radical cyclization, enables rapid construction of the isotwistane core. DFT-guided analysis revealed the challenge of late-stage C2-OH inversion and led to a successful chemo- and diastereoselective reduction of a caged hemiaminal ketone, providing access to the C2 epimer. This work establishes a unified asymmetric strategy for complex Lycopodium alkaloids and highlights the integration of computation with synthetic design.

RNA modifications are critical in regulating gene expression and cell functions by affecting RNA stability, splicing, translation, and degradation. The catalytic core of N⁶-adenosine-methyltransferase catalytic subunit METTL3 has emerged as a key enzyme in tumorigenesis by enhancing the translation efficiency of oncogenic transcripts, which is a promising therapeutic target for cancers, including acute myeloid leukemia. In this study, we presented a novel METTL3 inhibitory bioactivity (pIC₅₀) prediction model (ML3-mix-DPLIFE) by combining machine learning, protein–ligand docking, and protein–ligand interaction analysis, through encoding the conventional physicochemical properties, chemical fingerprint, and the docking-based protein–ligand interaction features (DPLIFE) with leveraging auto-stacking 6 algorithms. A feature selection algorithm further optimized the model (ML3-mix-DPLIFE-FS) and obtained a promising mean squared error (MSE) of 0.261 and a Pearson’s correlation coefficient (CC) of 0.853 on an independent test dataset, and identified 8 residues critical for ligand interactions with METTL3. To further test the model, the pIC₅₀s of recently reported inhibitors were predicted using the ML3-mix-DPLIFE-FS model, and a good MSE of 0.418 and CC of 0.727 were obtained. This innovative strategy seamlessly integrates machine learning prediction with structural biology insights and reveals a novel way to identify key protein–ligand interactions for further structural rational drug design.

The influence of allylic substituent orientation on the six-membered fused ring, as well as the steric hindrance at the alkene bridge (R¹ and R²) and bridgehead (R³), on the thiol-mediated acyl radical rearrangement/cyclization of bicyclo[2.2.2]octenone was investigated. A combined analysis using density functional theory calculations and interaction region indicator analysis suggests that reaction selectivity is driven by functional group noncovalent interactions.

Tumor-associated macrophages play an important role in cancer progression and immunosuppression, making their receptors promising therapeutic targets. MerTK, a TAM receptor, regulates macrophage efferocytosis and polarization, and its inhibition holds potential for tumor growth suppression and immune modulation. However, Tyro3, another TAM receptor, is involved in neurogenesis, highlighting the need to selectively target MerTK while avoiding Tyro3 inhibition to prevent neurotoxicity. In this study, we present a novel strategy for designing MerTK-selective inhibitors by modulating the conformational dynamics of its αC helix. By integrating structural biology, medicinal chemistry, protein stabilization assays, and molecular docking studies, we identified compound 11, which demonstrates potent inhibition and selectivity for MerTK. Pharmacokinetic evaluations and in vivo studies further reveal compound 11 as a promising candidate for further development. Our findings not only advance the understanding of the MerTK-specific mechanism but also propose a strategy for designing selective kinase inhibitors targeting the αC helix conformation.

Pancreatic cancer is an aggressive malignancy with a poor prognosis and limited treatment options. Cdc‐like kinase 4 (CLK4), a kinase that regulates alternative splicing by phosphorylating spliceosome components, is implicated in aberrant splicing events driving pancreatic cancer progression. In this study, we established a computational model that integrates pharmacological interactions of CLK4 inhibitors with an improved hit rate. Through this model, we identified a novel CLK4 inhibitor, compound 150441, with a 50% inhibitory concentration (IC₅₀) value of 21.4 nm. Structure‐activity relationship analysis was performed to investigate key interactions and functional groups. Kinase profiling revealed that compound 150441 is selective for CLK4. Subsequent in vitro assays demonstrated that this inhibitor effectively suppressed cell growth and viability of pancreatic cancer cells. In addition, it inhibited the phosphorylation of key splicing factors, including serine‐ and arginine‐rich splicing factor (SRSF) 4 and SRSF6. Cell cycle analysis further indicated that the compound induced G2/M arrest, leading to apoptosis. RNA‐seq analysis revealed that the compound induced significant changes in alternative splicing and key biological pathways, including RNA processing, DNA replication, DNA damage, and mitosis. These findings suggest that compound 150441 has promising potential for further development as a novel pancreatic cancer treatment.

Pannexin 1 (PANX1) forms cell‐surface channels capable of releasing signaling metabolites for diverse patho‐physiological processes. While inhibiting dysregulated PANX1 has been proposed as a therapeutic strategy for many pathological conditions, including inflammatory bowel disease (IBD), low efficacy, or poor specificity of classical PANX1 inhibitors introduces uncertainty for their applications in basic and translational research. Here, hit‐to‐lead optimization is performed and a naphthyridone, compound 12, is identified as a new PANX1 inhibitor with an IC₅₀ of 0.73 µm that does not affect pannexin‐homologous LRRC8/SWELL1 channels. Using structure–activity relationship analysis, mutagenesis, cell thermal shift assays, and molecular docking, it is revealed that compound 12 directly engages PANX1 Trp74 residue. Using a dextran sodium sulfate mouse model of IBD, it is found that compound 12 markedly reduced colitis severity, highlighting new PANX1 inhibitors as a proof‐of‐concept treatment for IBD. These data describe the mechanism of action for a new PANX1 inhibitor, uncover the binding site for future drug design, and present a targeted strategy for treating IBD.

The development of opioid analgesics with reduced adverse effects is an unmet need. In a previous study, we discovered a unique combination of BPRMU191 and morphinan antagonists that produced potent antinociception with reduced adverse effects after central administration (intrathecal or intracerebroventricular). BPRMU191/naltrexone exhibits notable in vitro and in vivo pharmacological properties. However, the poor blood-brain barrier penetrative ability of BPRMU191 restricts its clinical application. In this study, we utilized a prodrug strategy to deliver sufficient brain concentrations of BPRMU191 and selected compound 2 (DBPR116) with the best physicochemical and pharmacological properties among other in vivo active prodrugs. The in vivo pharmacological studies of compound 2/naltrexone, including thermally stimulated pain, cancer pain, constipation, sedation, psychological dependence, heart rate, and respiratory frequency measurements, demonstrated that it was a safer opioid analgesic than morphine in pain control.

Pannexin 1 (PANX1) forms cell-surface channels capable of releasing signaling metabolites for diverse patho-physiological processes. While inhibiting dysregulated PANX1 is proposed as a therapeutic strategy for many pathological conditions, including inflammatory bowel disease (IBD), low efficacy or poor specificity of classical PANX1 inhibitors introduces uncertainty for their applications in basic and translational research. Here, we performed hit-to-lead optimization and identified a naphthyridone, compound 12 , as a new PANX1 inhibitor with an IC ₅₀ of 0.73 μM that does not affect pannexin-homologous LRRC8/SWELL1 channels. Using structure-activity relationship analysis, mutagenesis, cell thermal shift assays, and molecular docking, we revealed that compound 12 directly engages PANX1 Trp74 residue. Using a dextran sodium sulfate mouse model of IBD, we found that compound 12 markedly reduced colitis severity, highlighting new PANX1 inhibitors as a proof-of-concept treatment for IBD. These data describe the mechanism of action for a new PANX1 inhibitor, identify the binding site for future drug design, and present a targeted strategy for treating IBD. Teaser: A specific PANX1 inhibitor presents a proof-of-concept treatment for inflammatory bowel disease.