Mining for METTL3 inhibitors to suppress cancer.
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ABSTRACT:
SUBMITTER: Li J
PROVIDER: S-EPMC8197751 | biostudies-literature | 2021 Jun
REPOSITORIES: biostudies-literature
Publications
Mining for METTL3 inhibitors to suppress cancer.
Li Jiazhi J Gregory Richard I RI
Nature structural & molecular biology 20210601 6
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Project description:The methylase METTL3 is the writer enzyme of the N6 -methyladenosine (m6 A) modification of RNA. Using a structure-based drug discovery approach, we identified a METTL3 inhibitor with potency in a biochemical assay of 280 nM, while its enantiomer is 100 times less active. We observed a dose-dependent reduction in the m6 A methylation level of mRNA in several cell lines treated with the inhibitor already after 16 h of treatment, which lasted for at least 6 days. Importantly, the prolonged incubation (up to 6 days) with the METTL3 inhibitor did not alter levels of other RNA modifications (i. e., m1 A, m6 Am , m7 G), suggesting selectivity of the developed compound towards other RNA methyltransferases.
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Project description:Drug resistance is an important open problem in cancer treatment. In recent years, the heat shock protein HSP27 (HSPB1) was identified as a key player driving resistance development. HSP27 is overexpressed in many cancer types and influences cellular processes such as apoptosis, DNA repair, recombination, and formation of metastases. As a result cancer cells are able to suppress apoptosis and develop resistance to cytostatic drugs. To identify HSP27 inhibitors we follow a novel computational drug repositioning approach. We exploit a similarity between a predicted HSP27 binding site to a viral thymidine kinase to generate lead inhibitors for HSP27. Six of these leads were verified experimentally. They bind HSP27 and down-regulate its chaperone activity. Most importantly, all six compounds inhibit development of drug resistance in cellular assays. One of the leads - chlorpromazine - is an antipsychotic, which has a positive effect on survival time in human breast cancer. In summary, we make two important contributions: First, we put forward six novel leads, which inhibit HSP27 and tackle drug resistance. Second, we demonstrate the power of computational drug repositioning.
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Project description:BackgroundCachexia, a syndrome of muscle atrophy, adipose loss, and anorexia, is associated with reduced survival in cancer patients. The colon adenocarcinoma C26c20 cell line secretes the cytokine leukemia inhibitory factor (LIF) which induces cachexia. We characterized how LIF promotes cachexia-associated weight loss and anorexia in mice through JAK-dependent changes in adipose and hypothalamic tissues.MethodsCachexia was induced in vivo with the heterotopic allotransplanted administration of C26c20 colon adenocarcinoma cells or the intraperitoneal administration of recombinant LIF in the absence or presence of JAK inhibitors. Blood, adipose, and hypothalamic tissues were collected and processed for cyto/adipokine ELISAs, immunoblot analysis, and quantitative RT-PCR. Cachexia-associated lipolysis was induced in vitro by stimulating differentiated adipocytes with recombinant LIF or IL-6 in the absence or presence of lipase or JAK inhibitors. These adipocytes were processed for glycerol release into the media, immunoblot analysis, and RT-PCR.ResultsTumor-secreted LIF induced changes in adipose tissue expression and serum levels of IL-6 and leptin in a JAK-dependent manner influencing cachexia-associated adipose wasting and anorexia. We identified two JAK inhibitors that block IL-6 family-mediated adipocyte lipolysis and IL-6 induction using an in vitro cachexia lipolysis assay. JAK inhibitors administered to the in vivo C26c20 cancer cachexia mouse models led to 1) a decrease in STAT3 phosphorylation in hypothalamic and adipose tissues, 2) a reverse in the cachexia serum cyto/adipokine signature, 3) a delay in cancer cachexia-associated anorexia and adipose loss, and 4) an improvement in overall survival.ConclusionsJAK inhibitors suppress LIF-associated adipose loss and anorexia in both in vitro and in vivo models of cancer cachexia.
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