PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSIONS: CUDC-907 may offer improved therapeutic benefits through simultaneous, sustained disruption of multiple oncogenic signaling networks.
PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: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. CONCLUSIONS:CUDC-907 may offer improved therapeutic benefits through simultaneous, sustained disruption of multiple oncogenic signaling networks.
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Authors: Yanxin Pei; Kun-Wei Liu; Jun Wang; Alexandra Garancher; Ran Tao; Lourdes A Esparza; Donna L Maier; Yoko T Udaka; Najiba Murad; Sorana Morrissy; Huriye Seker-Cin; Sebastian Brabetz; Lin Qi; Mari Kogiso; Simone Schubert; James M Olson; Yoon-Jae Cho; Xiao-Nan Li; John R Crawford; Michael L Levy; Marcel Kool; Stefan M Pfister; Michael D Taylor; Robert J Wechsler-Reya Journal: Cancer Cell Date: 2016-03-14 Impact factor: 31.743
Authors: Sharmistha Pal; David Kozono; Xiaodong Yang; Wojciech Fendler; Whitney Fitts; Jing Ni; John A Alberta; Jean Zhao; Kevin X Liu; Jie Bian; Nathalene Truffaux; William A Weiss; Adam C Resnick; Pratiti Bandopadhayay; Keith L Ligon; Steven G DuBois; Sabine Mueller; Dipanjan Chowdhury; Daphne A Haas-Kogan Journal: Cancer Res Date: 2018-05-14 Impact factor: 12.701