ABSTRACT
Overcoming acquired drug resistance is a primary challenge in cancer treatment. Notably, more than 50% of patients with BRAFV600E cutaneous metastatic melanoma (CMM) eventually develop resistance to BRAF inhibitors. Resistant cells undergo metabolic reprogramming that profoundly influences therapeutic response and promotes tumor progression. Uncovering metabolic vulnerabilities could help suppress CMM tumor growth and overcome drug resistance. Here we identified a drug, HA344, that concomitantly targets two distinct metabolic hubs in cancer cells. HA344 inhibited the final and rate-limiting step of glycolysis through its covalent binding to the pyruvate kinase M2 (PKM2) enzyme, and it concurrently blocked the activity of inosine monophosphate dehydrogenase, the rate-limiting enzyme of de novo guanylate synthesis. As a consequence, HA344 efficiently targeted vemurafenib-sensitive and vemurafenib-resistant CMM cells and impaired CMM xenograft tumor growth in mice. In addition, HA344 acted synergistically with BRAF inhibitors on CMM cell lines in vitro. Thus, the mechanism of action of HA344 provides potential therapeutic avenues for patients with CMM and a broad range of different cancers. SIGNIFICANCE: Glycolytic and purine synthesis pathways are often deregulated in therapy-resistant tumors and can be targeted by the covalent inhibitor described in this study, suggesting its broad application for overcoming resistance in cancer.
Subject(s)
Aminoimidazole Carboxamide/analogs & derivatives , Carrier Proteins/antagonists & inhibitors , IMP Dehydrogenase/antagonists & inhibitors , Melanoma/drug therapy , Membrane Proteins/antagonists & inhibitors , Ribonucleotides/pharmacology , Skin Neoplasms/drug therapy , Aged , Aminoimidazole Carboxamide/pharmacology , Animals , Cell Line, Tumor , Female , HEK293 Cells , Humans , Melanoma/enzymology , Melanoma/pathology , Mice , Mice, Nude , Random Allocation , Skin Neoplasms/enzymology , Skin Neoplasms/pathology , Thyroid Hormones , Xenograft Model Antitumor Assays , Thyroid Hormone-Binding Proteins , Melanoma, Cutaneous MalignantABSTRACT
A series of nucleoside analogues bearing a 1,4,5-trisubstituted-1,2,3-triazole aglycone was synthesized using a straightforward click/electrophilic addition or click/oxidative coupling tandem procedures. SAR analysis, using cell culture assays, led to the discovery of a series of compounds belonging to the 5-alkynyl-1,2,3-triazole family that exhibits potent antileukemic effects on several hematologic malignancies including chronic myeloid leukemia (CML) and myelodysplastic syndromes (MDS) either sensitive or resistant to their respective therapy. Compound 4a also proved efficient in vivo on mice xenografted with SKM1-R MDS cell line. Additionally, some insights in its mode of action revealed that this compound induced cell death by caspase and autophagy induction.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Glycosides/chemistry , Glycosides/pharmacology , Leukemia, Myeloid/drug therapy , Myelodysplastic Syndromes/drug therapy , Animals , Antineoplastic Agents/therapeutic use , Autophagy/drug effects , Cell Line, Tumor , Drug Resistance, Neoplasm , Female , Glycosides/therapeutic use , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Mice, Nude , Triazoles/chemistry , Triazoles/pharmacology , Triazoles/therapeutic use , Tumor Cells, CulturedABSTRACT
We have discovered and developed a series of molecules (thiazole benzenesulfonamides). HA15, the lead compound of this series, displayed anti-cancerous activity on all melanoma cells tested, including cells isolated from patients and cells that developed resistance to BRAF inhibitors. Our molecule displayed activity against other liquid and solid tumors. HA15 also exhibited strong efficacy in xenograft mouse models with melanoma cells either sensitive or resistant to BRAF inhibitors. Transcriptomic, proteomic, and biochemical studies identified the chaperone BiP/GRP78/HSPA5 as the specific target of HA15 and demonstrated that the interaction increases ER stress, leading to melanoma cell death by concomitant induction of autophagic and apoptotic mechanisms.
