C646, p300/CBP Inhibitor

• CAT Number: I003171
• CAS Number: 328968-36-1
• Molecular Formula: C₂₄H₁₉N₃O₆
• Molecular Weight: 445.42
• Purity: ≥95%
• Target: Histone Acetyltransferases
• Solubility: DMSO: ≥ 36 mg/mL
• Storage: Store at -20C
• IC50: 400 nM(Ki) [1]
• InChI: InChI=1S/C24H19N3O6/c1-13-10-20(21(27(31)32)11-14(13)2)22-9-8-18(33-22)12-19-15(3)25-26(23(19)28)17-6-4-16(5-7-17)24(29)30/h4-12H,1-3H3,(H,29,30)/b19-12-
• InChIKey: HEKJYZZSCQBJGB-UNOMPAQXSA-N
• SMILES: CC1=C(C=C(C(=C1)C2=CC=C(O2)C=C3C(=NN(C3=O)C4=CC=C(C=C4)C(=O)O)C)[N+](=O)[O-])C

C646 is a selective competitive histone acetyltransferase p300 inhibitor with Ki of 400 nM; less potent for other acetyltransferases.IC50 value: 400 nM(Ki) [1]Target: p300 inhibitorin vitro: C646 treatment reduces histone H3 and H4 acetylation levels and abrogates TSA-induced acetylation in cells. The melanoma line WM35 and the lung cancer line H23 were quite susceptible to C646 treatment with Lys-CoA-Tat showing modest inhibitory effects in these cells. Notably, the immortalized murine fibroblast cell line, NIH3T3, was not inhibited by C646 at 20 μM suggesting a differential effect on the malignant cells evaluated [1].C646 sensitized A549, H460 and H157 cells to IR with a dose enhancement ratio at 10% surviving fraction of 1.4, 1.2 and 1.2, respectively. C646 did not radiosensitize HFL-III cells. In A549 cells, but not in HFL-III cells, C646 (i) enhanced mitotic catastrophe but not apoptosis, necrosis, or senescence after IR; (ii) increased the hyperploid cell population after IR; and (iii) suppressed the phosphorylation of CHK1 after IR [2]. In the presence of the specific inhibitor of p300 acetyltransferase activity, C646, EDAG was unable to accelerate erythroid differentiation, indicating an involvement of p300 acetyltransferase activity in EDAG-induced erythroid differentiation [3]. C646 inhibited cellular proliferation, reduced colony formation, evoked partial cell cycle arrest in G1 phase, and induced apoptosis in AE-positive AML cell lines and primary blasts isolated from leukemic mice and AML patients [4].in vivo: C646 infused into the ILPFC immediately after weak extinction training enhances the consolidation of fear extinction memory [5]. C646 attenuated mechanical allodynia and thermal hyperalgesia, accompanied by a suppressed COX-2 expression, in the spinal cord [6].

Reference

1:The histone acetyltransferase p300 inhibitor C646 reduces pro-inflammatory gene expression and inhibits histone deacetylases. van den Bosch T, Boichenko A, Leus NG, Ourailidou ME, Wapenaar H, Rotili D, Mai A, Imhof A, Bischoff R, Haisma HJ, Dekker FJ.Biochem Pharmacol. 2016 Feb 15;102:130-40. doi: 10.1016/j.bcp.2015.12.010. Epub 2015 Dec 21. PMID: 26718586 Free PMC Article2:C646, a Novel p300/CREB-Binding Protein-Specific Inhibitor of Histone Acetyltransferase, Attenuates Influenza A Virus Infection. Zhao D, Fukuyama S, Sakai-Tagawa Y, Takashita E, Shoemaker JE, Kawaoka Y.Antimicrob Agents Chemother. 2015 Dec 28;60(3):1902-6. doi: 10.1128/AAC.02055-15. PMID: 26711748 Free PMC Article3:Histone acetyltransferase inhibitor C646 reverses epithelial to mesenchymal transition of human peritoneal mesothelial cells via blocking TGF-β1/Smad3 signaling pathway in vitro. Yang Y, Liu K, Liang Y, Chen Y, Chen Y, Gong Y.Int J Clin Exp Pathol. 2015 Mar 1;8(3):2746-54. eCollection 2015. PMID: 26045780 Free PMC Article4:C646, a selective small molecule inhibitor of histone acetyltransferase p300, radiosensitizes lung cancer cells by enhancing mitotic catastrophe. Oike T, Komachi M, Ogiwara H, Amornwichet N, Saitoh Y, Torikai K, Kubo N, Nakano T, Kohno T.Radiother Oncol. 2014 May;111(2):222-7. doi: 10.1016/j.radonc.2014.03.015. Epub 2014 Apr 17. PMID: 24746574 5:A histone acetyltransferase p300 inhibitor C646 induces cell cycle arrest and apoptosis selectively in AML1-ETO-positive AML cells. Gao XN, Lin J, Ning QY, Gao L, Yao YS, Zhou JH, Li YH, Wang LL, Yu L.PLoS One. 2013;8(2):e55481. doi: 10.1371/journal.pone.0055481. Epub 2013 Feb 4. PMID: 23390536 Free PMC Article