Syrbactin-class dual constitutive- and immuno-proteasome inhibitor TIR-199 impedes myeloma-mediated bone degenerationin vivo

Abstract

Proteasome-addicted neoplastic malignancies present a considerable refractory and relapsed phenotype with patients exhibiting drug-resistance and high mortality rates. To counter this global problem, novel proteasome-based therapies are being developed. In the current study we extensively characterize TIR-199, a syrbactin-class proteasome inhibitor derived from a plant virulence factor of bacterium Pseudomonas syringae pv syringae. We report that TIR-199 is a potent constitutive and immunoproteasome inhibitor, capable of inducing cell death in multiple myeloma, triple-negative breast cancer and non-small cell lung cancer lines, effectively inhibit proteasome in primary myeloma cells of patients, and bypass the PSMB5 A49T+A50V bortezomib-resistant mutant. TIR-199 treatment leads to accumulation of canonical proteasome substrates in cells, it is specific, and does not inhibit 50 other enzymes tested in vitro. The drug exhibits synergistic cytotoxicity in combination with proteasome-activating-kinase DYRK2 inhibitor LDN192960. Furthermore, low dose TIR-199 exhibits in vivo activity in delaying myeloma-mediated bone degeneration in a mouse xenograft model. Together, our data indicates that proteasome inhibitor TIR-199 could indeed be a promising next generation drug within the repertoire of proteasome-based therapeutics.

One-pot two-step catalytic synthesis of 6-amino-2-pyridone-3,5-dicarbonitriles enabling anti-cancer bioactivity

“…MDA-MB-231, 23 A549 22 and HEPG2 24 cancer cell lines, as well as primary patient-derived glioblastoma cells GBM6 and GBM22, were used in order to assess the anti-cancer properties of the compounds in vitro using cell viability assays. MDA-MB-231 is a triple-negative breast cancer epithelial cell line, A549 is a non-small cell lung cancer cell line and HEPG2 is a hepatocellular carcinoma cell line ( Fig.…”

“…Consequently, we observed anti-cancer cytotoxicity of the lead compound 5a and attempted to establish similar biological activity of the derivatives of 5a to establish the best derivative for future medicinal chemistry efforts. Although the current series of 16 derivatives were not predicted to be blood–brain barrier penetrant, we explored the potential of combining a 6-amino-2-pyridone-3,5-dicarbonitrile with clinically relevant BBB-penetrant small molecules 18–22 to establish potency for future medicinal chemistry efforts to optimise a BBB-penetrant drug.…”

Dual inhibition of HSF1 and DYRK2 impedes cancer progression

“…MDA-MB-231 HSF1 knock-out and DYRK2 knock-out cells were generated previously [ 14 ]. MM.1S and KMS18 cells were cultured as stated previously [ 20 , 21 ]. Briefly, parental- or bortezomib-resistant MM.1S and KMS18 cells were maintained in RPMI-1640 with 10% FBS and 1% penicillin and streptomycin.…”

Microwave-assisted multicomponent synthesis of antiproliferative 2,4-dimethoxy-tetrahydropyrimido[4,5-b]quinolin-6(7H)-ones

“…1e ). 26–32 2,4-dimethoxy-THPQs were then evaluated for in vitro antiproliferative activity against six human tumour cell lines. Furthermore, the most potent 2,4-dimethoxy-THPQs are evaluated by in silico ADMET and drug-likeness properties.…”