Structure-activity Relationship And The Synthesis Of Novel Histone Acetyltransferase P300Inhibitors

A growing body of evidence suggests that p300histone acetyltransferase playsimportant roles in cancer cell differentiation and proliferation. Here, we employedmedicinal chemistry and organic synthesis method to synthesize and modify the leadcompounds obtained from a screening library containing approximate100,000diversedruglike compounds or designed by MOE. More than50compounds were synthesized forthe inhibition of p300HAT domain experimental testing.The biological activity of the test showed that4-R~2-2-methyl-N-R~1-3,4-dihydro-2H-benzo [b][1,4] thiazine-7-sulfonamides represented a novel structural scaffoldfor p300HAT inhibitors. Based on its predicted binding pose, we investigated its bindingcharacteristics by designing two series of structural modifications and onecompound,4-acetyl-N-benzyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-sulfonami-de,shown as the optimal inhibitor with an IC50value of3.4μM which was more potentthan the reported compouds C646(IC50=6.0μM). However, other novel structuralscaffolds designed by MOE for p300HAT inhibitors, such as R~1-2-(2-((4-R~2-phenyl)-thionicotinamide) acetates,2-methyl-N-R-benzo [d] thiazol-6-sulfonamides,uracil compounds, naphthyl sulfonamides, benzene sulfonamides, benzamides did notshow promise as structural scaffolds for p300HAT inhibitors.The obtained structure-activity relationship results showed that sulfonamide group(-SO2-NH-) was the essential group of the biological activity in4-R~2-2-methyl-N-R~1-3,4-dihydro-2H-benzo [b][1,4] thiazine-7-sulfonamides. Thesulfonamide group mimiced the phosphate group in acetyl-CoA, and formed exactly thesame hydrogen bonds with Arg1410, Trp1466and Thr1411, the hydrogen bond acceptorinteracting with Gln1455was important (hereby the acetyl group), and the hydrophobicinteraction with Arg1462(hereby the benzyl group) was required. The results wereconsistent with the predicted binding model. We expect that the identified novel p300histone acetyltransferase inhibitors will serve as starting points for further development ofmore potent and specific histone acetyltransferase inhibitors.