Jiangying Cao

Proprotein convertase subtilisin/kexin 9 (PCSK9) mediating the degradation of the hepatic low‐density lipoprotein receptor (LDLR), has emerged as a novel therapeutic target for the treatment of hyperlipidemia. Herein, to disrupt the protein‐protein interactions (PPIs) between PCSK9 and LDLR, a total of 43 compounds were designed and synthesized by structural modification of previous derived PCSK9 inhibitors. In the PCSK9‐LDLR PPI interfering test, compounds B7 , B23 , and B27 showed inhibitory potency with IC ₅₀ values of 8.86 μM, 3.95 μM, and 5.02 μM, respectively, compared with the positive control SBC‐115,337 (IC ₅₀ value of 11.36 μM). Molecular docking predicted binding mode of compound B27 on the PCSK9‐LDLR interaction interface, and hydrophobic interactions play an important role in the binding of B27 to PCSK9. Moreover, compounds B7 , B23 , and especially B27 restored the expression of LDLR and increased LDL uptake of HepG2 cell in the presence of PCSK9. Collectively, lead compounds with lipid‐lowering potential were developed for further design of PCSK9‐LDLR PPI inhibitors.

Novel SIRT3 inhibitors were identified via structural modification for the treatment of MLL-rearranged leukemia.

A new leucine ureido derivative compound 3 exhibited potent antitumor properties, excellent in vitro stability and in vivo pharmacokinetic properties, was a promising lead for further development.

Aminopeptidase N (APN) was closely associated with cancer invasion, metastasis, and angiogenesis. Therefore, APN inhibitors have attracted more and more attention of scientists as antitumor agents. In the current study, we designed, synthesized, and evaluated one new series of pyrazoline-based hydroxamate derivatives as APN inhibitors. Moreover, the structure–activity relationships of those were discussed in detail. 2,6-Dichloro substituted compound 14o with R₁ = CH₃, showed the best capacity for inhibiting APN with an IC₅₀ value of 0.0062 ± 0.0004 μM, which was three orders of magnitude better than that of the positive control bestatin. Compound 14o possessed both potent anti-proliferative activities against tumor cells and potent anti-angiogenic activity. At the same concentration of 50 μM, compound 14o exhibited much better capacity for inhibiting the micro-vessel growth relative to bestatin in the rat thoracic aorta ring model. Additionally, the putative interactions of 14o with the active site of APN are also discussed. The hydroxamate moiety chelated the zinc ion and formed four hydrogen bonds with His²⁹⁷, Glu²⁹⁸ and His³⁰¹. Meanwhile, the terminal phenyl group and another phenyl group of 14o interacted with S₂′ and S₁ pockets via hydrophobic effects, respectively.

With five histone deacetylase (HDAC) inhibitors approved for cancer treatment, proteolysis-targeting chimeras (PROTACs) for degradation of HDAC are emerging as an alternative strategy for HDAC-targeted therapeutic intervention. Herein, three bestatin-based hydroxamic acids (P1, P2 and P3) were designed, synthesized and biologically evaluated to see if they could work as HDAC degrader by recruiting cellular inhibitor of apoptosis protein 1 (cIAP1) E3 ubiquitin ligase. Among the three compounds, the bestatin-SAHA hybrid P1 exhibited comparable even more potent inhibitory activity against HDAC1, HDAC6 and HDAC8 relative to the approved HDAC inhibitor SAHA. It is worth noting that although P1 could not lead to intracellular HDAC degradation after 6 h of treatment, it could dramatically decrease the intracellular levels of HDAC1, HDAC6 and HDAC8 after 24 h of treatment. Intriguingly, the similar phenomenon was also observed in the HDAC inhibitor SAHA. Cotreatment with proteasome inhibitor bortezomib could not reverse the HDAC decreasing effects of P1 and SAHA, confirming that their HDAC decreasing effects were not due to protein degradation. Moreover, all three bestatin-based hydroxamic acids P1, P2 and P3 exhibited more potent aminopeptidase N (APN, CD13) inhibitory activities than the approved APN inhibitor bestatin, which translated to their superior anti-angiogenic activities. Taken together, a novel bestatin-SAHA hybrid was developed, which worked as a potent APN and HDAC dual inhibitor instead of a PROTAC.