title: Small-molecule inhibitors of acetyltransferase p300 identified by high-throughput screening are potent anticancer agents.
abstract: Acetyltransferase p300 (KAT3B) plays key roles in signaling cascades that support cancer cell survival and sustained proliferation. Thus, p300 represents a potential 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 μmol/L 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 the cellular paralog of p300 (CBP), p300/CBP-associated factor, and GCN5, but not to other acetyltransferases (KAT5, KAT6B, and KAT7), histone deacetylases, 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.
authors.affiliation: Department of Anatomy and Cell Biology, Shands Cancer Center and Genetics Institute, University of Florida College of Medicine, Gainesville, Florida 100235, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Yang
authors.forename: Christie E
authors.initials: CE
authors.lastname: Pinello
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.forename: Dawei
authors.initials: D
authors.lastname: Li
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Wang
authors.forename: Lisa Y
authors.initials: LY
authors.lastname: Zhao
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Jahn
authors.forename: Sanjay Adrian
authors.initials: SA
authors.lastname: Saldanha
authors.forename: Peter
authors.initials: P
authors.lastname: Chase
authors.forename: Jamie
authors.initials: J
authors.lastname: Planck
authors.forename: Kyla R
authors.initials: KR
authors.lastname: Geary
authors.forename: Haiching
authors.initials: H
authors.lastname: Ma
authors.forename: Brian K
authors.initials: BK
authors.lastname: Law
authors.forename: William R
authors.initials: WR
authors.lastname: Roush
authors.forename: Peter
authors.initials: P
authors.lastname: Hodder
authors.forename: Daiqing
authors.initials: D
authors.lastname: Liao
mesh_terms: D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D020134:Catalytic Domain; D002460:Cell Line; D004354:Drug Screening Assays, Antitumor; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D062105:Molecular Docking Simulation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D054852:Small Molecule Libraries; D023041:Xenograft Model Antitumor Assays; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D000970:Antineoplastic Agents; D054852:Small Molecule Libraries; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor