ACS Medicinal Chemistry Letters最新文献

We report the discovery of an imidazopyridine series of IRAK1/4/pan-FLT3 kinase inhibitors. Optimization of this series has produced compound 31 which displays potent and selective inhibition of IRAK1, IRAK4, FLT3, and all mutant forms of FLT3, as well as good in vitro ADME and pharmacokinetic properties. In a mouse xenograft model of AML, 31 produces survival prolongation equal to that of Gilteritinib, the leading marketed FLT3 inhibitor currently used to treat AML.

PCI-27483, originally developed as a potent and selective inhibitor of the serine protease Factor VIIa (FVIIa) in complex with tissue factor (TF), has demonstrated significant promise in cancer therapy. In addition to its primary mechanism of action, the presence of a sulfonamide moiety in the PCI-27483 structure suggests further activities through the inhibition of carbonic anhydrases (CAs), particularly the tumor-associated human (h)CA isoforms hCA IX and XII. This study investigates the inhibitory activity of PCI-27483 against the complete panel of active hCAs, highlighting its polypharmacological potential in cancer treatment. X-ray crystallography and molecular docking studies elucidated the structural features underlying its selective inhibitory activity toward hCA IX and XII, offering insights into its dual-targeting pathway.

PCI-27483, originally developed as a potent and selective inhibitor of the serine protease Factor VIIa (FVIIa) in complex with tissue factor (TF), has demonstrated significant promise in cancer therapy. In addition to its primary mechanism of action, the presence of a sulfonamide moiety in the PCI-27483 structure suggests further activities through the inhibition of carbonic anhydrases (CAs), particularly the tumor-associated human (h)CA isoforms hCA IX and XII. This study investigates the inhibitory activity of PCI-27483 against the complete panel of active hCAs, highlighting its polypharmacological potential in cancer treatment. X-ray crystallography and molecular docking studies elucidated the structural features underlying its selective inhibitory activity toward hCA IX and XII, offering insights into its dual-targeting pathway.

Prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) have been used for diagnostic molecular imaging/therapy of prostate cancer (PCa). To address tumor heterogeneity, we synthesized and evaluated a bispecific PSMA/GRPR ligand (3) combining PSMA-617 (1) and the GRPR antagonist RM2 (2) with the radiometal chelator DOTA. 3 was radiolabeled with ⁶⁸Ga ([⁶⁸Ga]Ga-3) and ¹⁷⁷Lu ([¹⁷⁷Lu]Lu-3). [⁶⁸Ga]Ga-3 was tested in the following PCa cell lines for receptor affinity, time kinetic cell-binding/specificity, and cell-internalization: PC-3 and LNCaP. Compared to the monomers (1 and 2), ligand 3 showed specific cell binding, similar receptor affinities, and higher lipophilicity, while its internalization rates and cell-binding were superior. Docking calculations showed that 3 can have binding interactions of PSMA-617 (1) inside the PSMA receptor funnel and RM2 (2) inside the GRPR. In vivo biodistribution studies for [⁶⁸Ga]Ga-3 showed dual targeting for PSMA(+) and GRPR(+) tumors and higher tumor uptake, faster pharmacokinetic, and lower kidney uptake compared to 1 and 2

Prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) have been used for diagnostic molecular imaging/therapy of prostate cancer (PCa). To address tumor heterogeneity, we synthesized and evaluated a bispecific PSMA/GRPR ligand (3) combining PSMA-617 (1) and the GRPR antagonist RM2 (2) with the radiometal chelator DOTA. 3 was radiolabeled with ⁶⁸Ga ([⁶⁸Ga]Ga-3) and ¹⁷⁷Lu ([¹⁷⁷Lu]Lu-3). [⁶⁸Ga]Ga-3 was tested in the following PCa cell lines for receptor affinity, time kinetic cell-binding/specificity, and cell-internalization: PC-3 and LNCaP. Compared to the monomers (1 and 2), ligand 3 showed specific cell binding, similar receptor affinities, and higher lipophilicity, while its internalization rates and cell-binding were superior. Docking calculations showed that 3 can have binding interactions of PSMA-617 (1) inside the PSMA receptor funnel and RM2 (2) inside the GRPR. In vivo biodistribution studies for [⁶⁸Ga]Ga-3 showed dual targeting for PSMA(+) and GRPR(+) tumors and higher tumor uptake, faster pharmacokinetic, and lower kidney uptake compared to 1 and 2.

Three 1-deoxynojirimycin (DNJ) derivatives (named C4-C6) including DNJ and tegafur (TGF) were designed and synthesized, and their antiproliferative effects were investigated. C4-C6, especially C6, exerted good lipophilicity, α-glucosidase inhibitory activity, and antitumor effects. Mechanism studies indicated that C6 significantly induced cell apoptosis and S-phase block and inhibited migration of HCT-116 cells. Besides, C6 induced mitochondrial damage by decreasing the mitochondrial membrane potential, improving the accumulation of ROS, upregulating the expression of Bax, and downregulating Bcl-2. Moreover, C6 induced excessive production of ROS to trigger oxidative stress, resulting in an increase in the level of MDA and NO, a decrease in the content of GSH and SOD, and an overexpression of Nrf2. Furthermore, C6 induced DNA damage by down-regulating the expression of thymidylate synthase. These results indicated that C6 is a potential antitumor agent and kills HCT-116 cells through DNA damage, mitochondrial dysfunction, and oxidative stress.

ST2 belongs to the interleukin 1 receptor family and is expressed in immune cells including certain CD4⁺ T cells and mast cells. Binding of ST2 with interleukin 33 (IL-33) induces downstream signaling that activates NF-κB pathway. Although the ST2/IL-33 axis exerts immune tolerance via expansion of regulator T cells, the same axis also activates a subset of immune cells to produce proinflammatory cytokines in host defense or in tissue repair. Here, we reported the development of ST2 inhibitors with improved inhibitory activities against ST2 and metabolic stability based on a previous lead, iST2-14e. Using the human mast cell line (LAD2), we showed that ST2 inhibitors mitigated ST2 upregulation and reduced IL-1β released through degranulation, demonstrating that small-molecule ST2 inhibitors effectively attenuated the ST2/IL-33 signaling in human mast cells. Further optimization of the compounds may lay the foundation for developing ST2 inhibitors for the treatment of mast cells mediated diseases.

ST2 belongs to the interleukin 1 receptor family and is expressed in immune cells including certain CD4⁺ T cells and mast cells. Binding of ST2 with interleukin 33 (IL-33) induces downstream signaling that activates NF-κB pathway. Although the ST2/IL-33 axis exerts immune tolerance via expansion of regulator T cells, the same axis also activates a subset of immune cells to produce proinflammatory cytokines in host defense or in tissue repair. Here, we reported the development of ST2 inhibitors with improved inhibitory activities against ST2 and metabolic stability based on a previous lead, iST2-14e. Using the human mast cell line (LAD2), we showed that ST2 inhibitors mitigated ST2 upregulation and reduced IL-1β released through degranulation, demonstrating that small-molecule ST2 inhibitors effectively attenuated the ST2/IL-33 signaling in human mast cells. Further optimization of the compounds may lay the foundation for developing ST2 inhibitors for the treatment of mast cells mediated diseases.

Newer generation HIV-1 maturation inhibitors have proven to be viable antiretroviral agents in the clinic. VH3739937, (VH-937, 24) is an advanced HIV-1 maturation inhibitor (MI) with a 4-cyanopyridyl ether replacing the fluorine present in the previous lead MI GSK3640254 (GSK254, 3). The introduction of aromatic methylene ethers α to the carboxylic acid moiety significantly enhanced the antiviral profile, with additional inhibitory effects observed toward the A364V mutation, the primary resistance mutation emerging in response to selective pressure by MIs. Structure-activity optimization led to the invention of VH-937, which combined the best overall antiviral profile with pharmacokinetic properties in animal models. These properties indicate the potential for infrequent dosing, a finding confirmed in initial clinical studies in humans that suggests its potential as a once-weekly dosing agent.

Three 1-deoxynojirimycin (DNJ) derivatives (named C4–C6) including DNJ and tegafur (TGF) were designed and synthesized, and their antiproliferative effects were investigated. C4–C6, especially C6, exerted good lipophilicity, α-glucosidase inhibitory activity, and antitumor effects. Mechanism studies indicated that C6 significantly induced cell apoptosis and S-phase block and inhibited migration of HCT-116 cells. Besides, C6 induced mitochondrial damage by decreasing the mitochondrial membrane potential, improving the accumulation of ROS, upregulating the expression of Bax, and downregulating Bcl-2. Moreover, C6 induced excessive production of ROS to trigger oxidative stress, resulting in an increase in the level of MDA and NO, a decrease in the content of GSH and SOD, and an overexpression of Nrf2. Furthermore, C6 induced DNA damage by down-regulating the expression of thymidylate synthase. These results indicated that C6 is a potential antitumor agent and kills HCT-116 cells through DNA damage, mitochondrial dysfunction, and oxidative stress.