Discovery And Activity Of Tetrahydro-β-carboline Derivatives Targeting USP15 Inhibition

Ubiquitination is highly efficient and selective degradation process of protein. Its reversible process is named deubiquitination, which is regulated by deubiquitinating enzymes (DUBs). Ubiquitin specific protease 15 (USP15), as one of DUBs, can promote tumor growth and metastasis by activating TGFβ signaling pathway. For example, the absence of USP15 can reduce the size of tumor in the glioblastoma, which suggests that USP15 could be regarded as a therapeutic target for cancer. Thus, USP15 inhibitors show great prospect in clinical medicine. However, the inhibitors specifically targeting USP15 have not been reported to date, except for PR-619, which was a broad inhibitor of DUBs. Discovery and identification of a series of inhibitors specifically targeting USP15 is our goal in this thesis.In our previous research, a novel series of tetrahydro-p-carboline derivatives were developed and found to inhibit TGFβ signaling pathway, which led to the antitumor growth and metastasis effects. It is reported that USP15 can promote the expression of TGFβ signaling pathway through deubiquitination of TGFP receptors. Thus, it is naturally supposed whether or not the series of compounds shows inhibition of USP15 enzymes. The results of biological screen experiments suggested that some of them showed potent inhibitory activities against USP15 enzymes, and several compounds indicated similar inhibitory effects with the same grade level compared to PR-619. Based on the initial structure-activity analysis, introduction of alcamines substituents and amino acid residues on phenyl ring of tetrahydro-β-carboline was found to promote their inhibitory effects. Thus more substitutes of the same class were explored. And finally several compounds were discovered and identified which showed similar inhibitory activities, and more importantly, they showed better specificity against USP15 compared to PR-619.According to the structure-activity analysis of the series compounds, the following conclusions were summarized. The substitution on 5-position was not preferred compared with corresponding ones on 6-,7- and 8-positions, among which there was no obvious biological activity difference. The electronic effects of substitutes show little effects on promoting its activities. The introduction of alcamines substituents can promote the inhibitory activities, among which straight chain structure is more preferred to branched ones. The oxygen atom is essential for the maintenance of biological activities. The introduction of amino acid residues can improve its activities, and α-structure is necessary. The structure inversion of amide bond can greatly reduce the biological activities.