Mechanism of p300 Specific Histone Acetyltransferase Inhibition by Small Molecules.

[摘要]：Dysfunction of histone acetyltransferases (HATs) leads to several diseases including cancer, diabetes, and asthma. Therefore, small mol. inhibitors and activators of HATs are being considered as new generation therapeutics. Here, we report the mol. mechanisms of p300 HAT inhibition by specific and non-specific HAT inhibitors: garcinol, isogarcinol, and 1 (LTK14). The p300 specific HAT inhibitor 1 behaves as a non-competitive inhibitor for both acetyl-CoA and histone, unlike non-specific HAT inhibitors garcinol and isogarcinol. The isothermal calorimetric data suggest that there is a high affinity enthalpy driven single binding site for 1 on p300HAT domain in contrast to two binding sites for garcinol and isogarcinol. Furthermore, the precise nature of mol. interactions was detd. by using fluorescence, docking, and mutational studies. On the basis of these observations, we have proposed the mechanisms of specific vs. non-specific HAT inhibition by these small mol. compds., which may be useful to design therapeutically favorable HAT inhibitors.

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