Supplementary Figures 1 - 9 from Cancer Network Disruption by a Single Molecule Inhibitor Targeting Both Histone Deacetylase Activity and Phosphatidylinositol 3-Kinase Signaling

Qian, Changgeng; Lai, Cheng-Jung; Bao, Rudi; Wang, Da-Gong; Wang, Jing; Xu, Guang-Xin; Atoyan, Ruzanna; Qu, Hui; Yin, Ling; Samson, Maria; Zifcak, Brian; Ma, Anna Wai See; DellaRocca, Steven; Borek, Mylissa; Zhai, Hai-Xiao; Cai, Xiong; Voi, Maurizio

doi:10.1158/1078-0432.22445738.v1

Supplementary Figures 1 - 9 from Cancer Network Disruption by a Single Molecule Inhibitor Targeting Both Histone Deacetylase Activity and Phosphatidylinositol 3-Kinase Signaling

journal contribution

posted on 2023-03-31, 17:03 authored by Changgeng Qian, Cheng-Jung Lai, Rudi Bao, Da-Gong Wang, Jing Wang, Guang-Xin Xu, Ruzanna Atoyan, Hui Qu, Ling Yin, Maria Samson, Brian Zifcak, Anna Wai See Ma, Steven DellaRocca, Mylissa Borek, Hai-Xiao Zhai, Xiong Cai, Maurizio Voi

PDF file, 348KB, Figure S1. Synergy between PI3K and HDAC pathway inhibition. Figure S2. CUDC-907 increases acetylation of histone H3 in cultured cancer cells. Figure S3. CUDC-907 increases tubulin acetylation in cultured cancer cells. Figure S4. CUDC-907 increases p53 acetylation in cultured cancer cells. Figure S5. CUDC-907 increases p21 levels in cultured cancer cells. Figure S6. CUDC-907 induces the accumulation of activated caspases-3 and -7. Figure S7. CUDC-907 induces the accumulation of annexin V binding sites. Figure S8. CUDC-907 induces a G2/M cell cycle arrest. Figure S9. CUDC-907 is orally bioavailable and shows intratumoral accumulation.

History

ARTICLE ABSTRACT

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. Clin Cancer Res; 18(15); 4104–13. ©2012 AACR.