Abstract PR16: A new class of small molecule acetyltransferase inhibitors discovered through high-throughput screening are potent anticancer agents with cancer-type specific activity

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-07, Vol.73 (13_Supplement), p.PR16-PR16
• Main Authors: Yang, Heng, Pinello, Christie E., Luo, Jian, Li, Dawei, Wang, Yunfei, Lisa, Zhao Y., Jahn, Stephan C., Saldanha, S. Adrian, Planck, Jamie, Geary, Kyla R., Ma, Haiching, Law, Brian K., Roush, William R., Hodder, Peter, Liao, Daiqing
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.CEC13-PR16

Acetyltransferase p300 (KAT3B) plays key roles in signaling cascades that support cancer cell survival and sustained proliferation. p300 is overexpressed in several types of cancer, which correlates with tumor progression. Thus, p300 represents a rational anticancer therapeutic target. To discover novel anticancer agents that target p300, we conducted a high-throughput screening campaign. A library of 622,079 compounds was assayed for cytotoxicity to the triple-negative breast cancer (TNBC) cell line MDA-MB-231 but not to the human mammary epithelial cells. The resulting compounds were tested in a biochemical assay for inhibiting the enzymatic activity of p300. One compound (L002, NSC764414) displayed an IC50 of 1.98 μM against p300 in vitro, inhibited acetylation of histones and p53, and suppressed STAT3 activation in cell-based assays. L002 could be docked to the active site of the p300 catalytic domain. Biochemical tests of a series of related compounds revealed functional groups that may impact inhibitory potency of L002 against p300. Interestingly, these analogs showed inhibitory activities against CBP (the cellular paralog of p300), PCAF and GCN5, but not to other acetyltransferases (KAT5, KAT6B and KAT7), histone deacetylases (HDACs) and histone methyltransferases. Among the NCI-60 panel of cancer cell lines, leukemia and lymphoma cell lines were extremely sensitive to L002, whereas it is toxic to only a limited number of cell lines derived from solid tumors. Notably, breast cancer cell lines, especially those derived from TNBC, were highly susceptible to L002. In vivo, it potently suppressed tumor growth and histone acetylation of MDA-MB-468 xenografts. Thus, these new acetyltransferase inhibitors are potential anticancer therapeutics with specific activities against breast cancer and hematological malignancies. This abstract is also presented as Poster B43. Citation Format: Heng Yang, Christie E. Pinello, Jian Luo, Dawei Li, Yunfei Wang, Zhao Y. Lisa, Stephan C. Jahn, S. Adrian Saldanha, Jamie Planck, Kyla R. Geary, Haiching Ma, Brian K. Law, William R. Roush, Peter Hodder, Daiqing Liao. A new class of small molecule acetyltransferase inhibitors discovered through high-throughput screening are potent anticancer agents with cancer-type specific activity. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr PR