Journal of Medicinal Chemistry最新文献

Protein arginine methyltransferase 5 (PRMT5) plays crucial roles in the regulation of various biological processes through the mono- and symmetric dimethylation of protein substrates. PRMT5 is overexpressed in various human cancers and its overexpression is associated with poor prognosis. We previously reported the first-in-class PRMT5 degrader, MS4322, which is also the only von Hippel-Lindau (VHL)-recruiting PRMT5 degrader to date. Here, we performed structure–activity relationship (SAR) studies exploring various linkers and ligands of VHL and PRMT5, which resulted in the best-in-class PRMT5 degrader, MS115 (compound 10). Compound 10 potently and selectively degraded PRMT5 and its coactivator, MEP50, in concentration-, time-, and ubiquitin-proteasome system-dependent manners. It displayed much improved PRMT5/MEP50 degradation potency over MS4322, which translated to better antiproliferative effect in both breast and prostate cancer cells. Overall, we discovered a highly potent and selective PRMT5/MEP50 complex degrader, which is an invaluable chemical biology tool and a potential cancer therapeutic.

Targeting programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway has been considered as one of the most promising strategies for tumor immunotherapy. However, single-target PD-1/PD-L1 inhibitors frequently exhibit limited efficacy, highlighting the urgent need for new therapies. Herein, a series of dual PD-L1/HDAC3 inhibitors were developed through a pharmacophore fusion strategy for the first time. Among them, compound PH3 was identified as the most promising dual PD-L1/HDAC3 inhibitor, with potent PD-1/PD-L1 inhibitory activity (IC₅₀ = 89.4 nM) and selective HDAC3 inhibitory activity (IC₅₀ = 107 nM). Moreover, PH3 exhibited superior in vitro antitumor activities and in vitro immune activation effects. Additionally, PH3 showed potent and dose-dependent antitumor efficacy in the B16-F10 melanoma mouse model without obvious toxicity. Furthermore, PH3 increased the infiltration of CD3⁺CD8⁺ and CD3⁺CD4⁺ cells in the tumor microenvironment. Collectively, PH3 represented a novel dual PD-L1/HDAC3 inhibitor deserving further investigation as a tumor immunotherapy agent.

Aberrant expression of the phosphatase SHP2 is implicated in numerous cancers, including KRAS G12D mutation driven PDAC. Although several SHP2 inhibitors have been reported, specific inhibitors with potent efficacy are not yet available. Given the elevated autophagy in PDAC, herein, we first designed novel SHP2 degraders through autophagosome-tethering compound strategy. Among them, the preferred 11n formed hydrogen bonds with Arg 111 and Glu 250 residues of SHP2 to enhance interactions between SHP2 and LC3. 11n also possessed great efficacy and selectivity against KRAS G12D mutant cancer cells versus the wild type. Moreover, the degradation caused by 11n manipulated the signaling pathways associated with cell apoptosis, metastasis, and invasion to inhibit the tumor growth both in vitro and in vivo. These findings not only generated a useful tool for exploring the potential of targeting SHP2 degradation but also offered promising candidates to develop novel drugs based on the autophagy mechanism.

Among the smaller substituents in the medicinal chemist’s toolbox, the hydroxy (OH) group can bestow one of the largest impacts in the drug-like properties of a molecule. A previous study showed that an H-to-OH structural modification effectively decreases lipophilicity, increases solubility, and decreases hERG inhibition. Despite these benefits, an OH group is not always recommended in drug molecules because it presents a metabolic “soft spot” for oxidation and glucuronidation in primary and secondary alcohols. Furthermore, the OH group presents challenges in permeability. In contrast, tertiary alcohols (3° ROH) often display an improved metabolic profile because oxidation at the 3° ROH is not possible, and the geminal alkyl groups could sterically shield the OH group from glucuronidation and permeability challenges. Through a series of matched molecular pairs, this Perspective highlights the 3° ROH as a motif that can reap the benefits but minimize the drawbacks of hydroxy groups in drug discovery.

Cancer stem cells (CSCs) are key contributors to tumor resistance, recurrence, and metastasis. Conventional chemotherapy often fails to target and eradicate CSCs, significantly impairing their therapeutic efficacy. Herein, we design and synthesize a photoactivated ferrocene-iridium(III) complex (Ir-3) to achieve immunotherapy against melanoma cells (including stem cells). In short, Ir-3 effectively targets mitochondria and dissociates under light irradiation to produce a cytotoxic Ir(III) photosensitizer and Fe²⁺ ions. They can generate reactive oxygen species by the Fenton reaction, robustly induce ferroptosis and autophagy, and eventually trigger immunogenic cell death in melanoma cells (including stem cells). Furthermore, under light exposure, Ir-3 effectively inhibits stem cell-related properties and promotes macrophage-mediated phagocytosis of melanoma stem cells. For in vivo studies, Ir-3 is encapsulated in DSPE-PEG 2000 to form tumor-targeting Ir-3@PEG nanoparticles. After photoactivation, Ir-3@PEG can significantly inhibit primary and distant tumors, effectively inhibit the stemness of melanoma stem cells, and induce innate and adaptive immune responses.

To discover new antimalarials, a screen of the Janssen Jumpstarter library against Plasmodium falciparum uncovered the N-acetamide indole hit class. The structure–activity relationship of this chemotype was defined and culminated in the optimized frontrunner analog WJM664, which exhibited potent asexual stage activity and high metabolic stability. Resistant selection and whole-genome sequencing revealed mutations in PfATP4, which was validated as the target by showing that analogs exhibited reduced potency against parasites with resistance-conferring mutations in PfATP4, a metabolomic signature similar to that of the PfATP4 inhibitor KAE609, and inhibition of Na⁺-dependent ATPase activity consistent with on-target inhibition of PfATP4. WJM664 inhibited gamete development and blocked parasite transmission to mosquitoes but exhibited low efficacy in aPlasmodium berghei mouse model, which was attributed to ATP4 species differentiation and its moderate systemic exposure. Optimization of these attributes is required for N-acetamide indoles to be pursued for development as a curative and transmission-blocking therapy.

Atherosclerosis is a multifaceted disease involving various cell types and complex mechanisms, and it is the main cause of cardiovascular disease. Proprotein convertase subtilisin/kexin type-9 (PCSK9) has been identified as an effective target for treating atherosclerosis; however, most current research focuses on biological drugs. Our work optimized the previously reported autophagosome-tethering compound OY3, and specifically, compound W6 induced PCSK9 degradation with a 5-fold increase in activity and a 6-fold increase in bioavailability. Compared to the currently marketed PCSK9 drug, siRNA, W6 demonstrated comparable antiatherosclerosis effects both in vivo and in vitro. W6 exhibited beneficial effects on hepatocytes, endothelial cells, macrophages, and vascular smooth muscle cells involved in the atherosclerosis process, making it a promising potential antiatherosclerosis drug. This work highlights the feasibility of ATTECs in degrading both intracellular and extracellular proteins, and our novel PCSK9-ATTEC W6 provides a valuable reference for the treatment of atherosclerotic diseases.