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|Ref Type||Journal Article|
|Authors||Han H, Jain AD, Truica MI, Izquierdo-Ferrer J, Anker JF, Lysy B, Sagar V, Luan Y, Chalmers ZR, Unno K, Mok H, Vatapalli R, Yoo YA, Rodriguez Y, Kandela I, Parker JB, Chakravarti D, Mishra RK, Schiltz GE, Abdulkadir SA|
|Title||Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy.|
|Date||2019 Nov 11|
|Abstract Text||Small molecules that directly target MYC and are also well tolerated in vivo will provide invaluable chemical probes and potential anti-cancer therapeutic agents. We developed a series of small-molecule MYC inhibitors that engage MYC inside cells, disrupt MYC/MAX dimers, and impair MYC-driven gene expression. The compounds enhance MYC phosphorylation on threonine-58, consequently increasing proteasome-mediated MYC degradation. The initial lead, MYC inhibitor 361 (MYCi361), suppressed in vivo tumor growth in mice, increased tumor immune cell infiltration, upregulated PD-L1 on tumors, and sensitized tumors to anti-PD1 immunotherapy. However, 361 demonstrated a narrow therapeutic index. An improved analog, MYCi975 showed better tolerability. These findings suggest the potential of small-molecule MYC inhibitors as chemical probes and possible anti-cancer therapeutic agents.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|MYCi975||NUCC-0200975||c-MYC Inhibitor 9||MYCi975 is an inhibitor of MYC that blocks the interaction between Myc and Max, which leads to reduced Myc stability, thereby potentially enhancing the antitumor immune response, and inhibiting colony formation and tumor growth (PMID: 31679823).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||leukemia||not applicable||Cytarabine + MYCi975||Preclinical - Cell line xenograft||Actionable||In a preclinical study, MYCi975 and Cytosar-U (cytarabine) combination treatment synergistically inhibited tumor growth in a cell line xenograft model of leukemia (PMID: 31679823).||31679823|
|Unknown unknown||prostate cancer||not applicable||MYCi975 + unspecified PD-1 antibody||Preclinical||Actionable||In a preclinical study, MYCi975 combined with an anti-PD1 therapy synergistically inhibited tumor growth in a mouse model of prostate cancer (PMID: 31679823).||31679823|
|Unknown unknown||leukemia||not applicable||MYCi975||Preclinical - Cell culture||Actionable||In a preclinical study, MYCi975 treatment inhibited viability of a leukemia cell line in culture (PMID: 31679823).||31679823|
|Unknown unknown||lung carcinoma||not applicable||MYCi975||Preclinical||Actionable||In a preclinical study, MYCi975 treatment inhibited tumor growth in a mouse model of Lewis lung carcinoma (PMID: 31679823).||31679823|