StarWise Therapeutics LLC

New drugs or therapeutic combinations are urgently needed against Mycobacterium abscessus . Previously, we demonstrated the potent activity of indole-2-carboxamides 6 and 12 against M. abscessus . We show here that these compounds act synergistically with imipenem and cefoxitin in vitro and increase the bactericidal activity of the β-lactams against M. abscessus . In addition, compound 12 also displays synergism with imipenem and cefoxitin within infected macrophages.

Introduction: Histone deacetylase 6 (HDAC6) is unique in comparison with other zinc-dependent HDAC family members. An increasing amount of evidence from clinical and preclinical research demonstrates the potential of HDAC6 inhibition as an effective therapeutic approach for the treatment of cancer, autoimmune diseases, as well as neurological disorders. The recently disclosed crystal structures of HDAC6-ligand complexes offer further means for achieving pharmacophore refinement, thus further accelerating the pace of HDAC6 inhibitor discovery in the last few years.Area covered: This review summarizes the latest clinical status of HDAC6 inhibitors, discusses pharmacological applications of selective HDAC6 inhibitors in neurodegenerative diseases, and describes the patent applications dealing with HDAC6 inhibitors from 2014-2019 that have not been reported in research articles.Expert opinion: Phenylhydroxamate has proven a very useful scaffold in the discovery of potent and selective HDAC6 inhibitors. However, weaknesses of the hydroxamate function such as metabolic instability and mutagenic potential limit its application in the neurological field, where long-term administration is required. The recent invention of oxadiazole-based ligands by pharmaceutical companies may provide a new opportunity to optimize the druglike properties of HDAC6 inhibitors for the treatment of neurodegenerative diseases.

Pancreatic ductal adenocarcinoma (PDAC) is a predominantly fatal common malignancy with inadequate treatment options. Glycogen synthase kinase 3β (GSK-3β) is an emerging target in human malignancies including PDAC.

Pancreatic cancer cell lines and patient-derived xenografts were treated with a novel GSK-3 inhibitor 9-ING-41 alone or in combination with chemotherapy. Activation of the DNA damage response pathway and S-phase arrest induced by gemcitabine were assessed in pancreatic tumor cells with pharmacologic inhibition or siRNA depletion of GSK-3 kinases by immunoblotting, flow cytometry, and immunofluorescence.

9-ING-41 treatment significantly increased pancreatic tumor cell killing when combined with chemotherapy. Inhibition of GSK-3 by 9-ING-41 prevented gemcitabine-induced S-phase arrest suggesting an impact on the ATR-mediated DNA damage response. Both 9-ING-41 and siRNA depletion of GSK-3 kinases impaired the activation of ATR leading to the phosphorylation and activation of Chk1. Mechanistically, depletion or knockdown of GSK-3 kinases resulted in the degradation of the ATR-interacting protein TopBP1, thus limiting the activation of ATR in response to single-strand DNA damage.

These data identify a previously unknown role for GSK-3 kinases in the regulation of the TopBP1/ATR/Chk1 DNA damage response pathway. The data also support the inclusion of patients with PDAC in clinical studies of 9-ING-41 alone and in combination with gemcitabine.