Description
L002 is an inhibitor of p300 histone acetyltransferase (KAT3B; IC
50 = 1.98 μM
in vitro). It has weaker inhibitory effects against PCAF and GCN5 (IC
50s = 35 and 34 μM, respectively) and is specific for p300 over a panel of additional acetyltransferases, deacetylases, and methyltransferases. L002 blocks acetylation of histones and p53 in cells treated with trichostatin A or etoposide, respectively, and reduces STAT3 phosphorylation, which requires p300-mediated acetylation of STAT3. It induces growth arrest and apoptosis in certain cancer cell lines and, when administered intraperitoneally in mice, suppresses the growth of triple-negative breast cancer xenografts.
Uses
L002 is an inhibitor of p300 histone acetyl transferase, which maintains weaker inhibitory effects against PCAF and GCN5. and is specific for p3000.
Biochem/physiol Actions
L002 (NSC764414) is an inhibitor of acetyltransferase p300, a lysine acetyltransferase that catalyzes acetyl group attachment to lysine residues of a variety of proteins including histones and p53, and acts as a critical coactivator of several oncogenic transcription factors involved in cancer cell survival and proliferation including STAT3, NF-kB, and hypoxia-inducible factor-1α (HIF-1α). L002 (NSC764414) was discovered from compounds assayed for cytotoxicity to the triple-negative breast cancer (TNBC) cell line MDA-MB-231 but not to the human mammary epithelial cells, then further screened for inhibition of p300. L002 has an in vitro IC50 of 1.98 μM for p300 with lesser inhibition of the GNAT (GCN5-related N-acetyltransferase) family, and no inhibition against the MYST family of histone acetyltransferases (HATs), histone deacetylases (HDACs), or histone methyltransferases (HMTs). L002 potently suppressed tumor growth and histone acetylation of MDA-MB-468 xenografts and leukemia and lymphoma cell lines.
in vivo
L002 (intraperitoneal injection; 20 μg/gm body weight; every 3rd day; 2 weeks) reverses hypertension-induced cardiac hypertrophy and fibrosis by treatment of mice after inducing hypertension for two weeks significantly.It also reduces the levels of perivascular and interstitial collagen in the myocardium compared to non-treated hypertensive mice[3].
| Animal Model: | Wild‐type C57BL/6 male mice planted with osmotic minipumps ( Angiotensin II 1500ng/kg/min) for 4 weeks[3] |
| Dosage: | 20μg/gm body weight; every 3rd day; 2 weeks |
| Administration: | Intraperitoneal injection |
| Result: | Reversed hypertension-induced cardiac fibrosis in mice. |
References
[1] HENG YANG. Small-molecule inhibitors of acetyltransferase p300 identified by high-throughput screening are potent anticancer agents.[J]. Molecular Cancer Therapeutics, 2013: 610-620. DOI:
10.1158/1535-7163.mct-12-0930[2] FUMITO KANADA. Histone acetyltransferase and Polo-like kinase 3 inhibitors prevent rat galactose-induced cataract.[J]. Scientific Reports, 2019: 20085. DOI:
10.1038/s41598-019-56414-x
