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|Ref Type||Journal Article|
|Authors||Qian C, Lai CJ, Bao R, Wang DG, Wang J, Xu GX, Atoyan R, Qu H, Yin L, Samson M, Zifcak B, Ma AW, DellaRocca S, Borek M, Zhai HX, Cai X, Voi M|
|Title||Cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2012 Aug 01|
|Abstract Text||Given that histone deacetylase (HDAC) inhibitors are known to induce multiple epigenetic modifications affecting signaling networks and act synergistically with phosphatidylinositol 3-kinase (PI3K) inhibitors, we developed a strategy to simultaneously inhibit HDACs and PI3K in cancer cells.We constructed dual-acting inhibitors by incorporating HDAC inhibitory functionality into a PI3K inhibitor pharmacophore. CUDC-907, a development candidate selected from these dual inhibitors, was evaluated in vitro and in vivo to determine its pharmacologic properties, anticancer activity, and mechanism of action.CUDC-907 potently inhibits class I PI3Ks as well as classes I and II HDAC enzymes. Through its integrated HDAC inhibitory activity, CUDC-907 durably inhibits the PI3K-AKT-mTOR pathway and compensatory signaling molecules such as RAF, MEK, MAPK, and STAT-3, as well as upstream receptor tyrosine kinases. CUDC-907 shows greater growth inhibition and proapoptotic activity than single-target PI3K or HDAC inhibitors in both cultured and implanted cancer cells.CUDC-907 may offer improved therapeutic benefits through simultaneous, sustained disruption of multiple oncogenic signaling networks.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|CUDC-907||Fimepinostat||HDAC Inhibitor 39 PI3K Inhibitor (Pan) 39||CUDC-907 (fimepinostat) is a dual PI3K and HDAC inhibitor, which prevents activation of the PI3K-AKT-mTOR signal transduction pathway, inhibits tumor cell growth, and promotes apoptosis in cancer cells (PMID: 22693356, PMID: 32459381).|
|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|
|PIK3CA mutant||hematologic cancer||sensitive||CUDC-907||Preclinical - Cell line xenograft||Actionable||In a preclinical study, CUDC-907 inhibited PIK3CA, blocked downstream AKT pathway activation, and induced apoptosis and cell cycle arrest in both PIK3CA wild-type and PIK3CA mutant human cancer cell lines and xenograft models of multiple solid and hematologic cancers (PMID: 22693356).||22693356|
|PTEN del||breast cancer||sensitive||CUDC-907||Preclinical - Cell culture||Actionable||In a preclinical study, CUDC-907 inhibited growth of breast cancer cells lines harboring Pten mutations and/or deletions (PMID: 22693356).||22693356|
|PTEN del||prostate cancer||sensitive||Pictilisib + Vorinostat||Preclinical||Actionable||In a preclinical study, GDC-0941 and Zolinza (vorinostat) acted synergistically to inhibit growth of a human prostate cancer cell line harboring a PTEN deletion in culture (PMID: 9661880, PMID: 22693356).||22693356 9661880|
|PIK3CA mutant||Advanced Solid Tumor||sensitive||CUDC-907||Preclinical - Cell line xenograft||Actionable||In a preclinical study, CUDC-907 inhibited PIK3CA, blocked downstream AKT pathway activation, and induced apoptosis and cell cycle arrest in both PIK3CA wild-type and PIK3CA mutant human cancer cell lines and xenograft models of multiple tumor types (PMID: 22693356).||22693356|
|PTEN mutant||breast cancer||sensitive||CUDC-907||Preclinical - Cell culture||Actionable||In a preclinical study, CUDC-907 inhibited growth of breast cancer cells lines harboring Pten mutations and/or deletions (PMID: 22693356).||22693356|
|PIK3CA mutant||breast cancer||sensitive||CUDC-907||Preclinical||Actionable||In a preclinical study, CUDC-907 inhibited growth of human breast cancer cell lines harboring PIK3CA mutations in culture (PMID: 22693356).||22693356|