Discovery of [1,2,3]triazolo[4,5-d]pyrimidine derivatives as highly potent, selective, and cellularly active USP28 inhibitors

Abstract

Ubiquitin specific peptidase 28 (USP28) is closely associated to the occurrence and development of various malignancies, and thus has been validated as a promising therapeutic target for cancer therapy. To date, only few USP28 inhibitors with moderate inhibitory activity have been reported, highly potent and selective USP28 inhibitors with new chemotypes remain to be discovered for pathologically investigating the roles of deubiquitinase. In this current study, we reported the synthesis and biological evaluation of new [1,2,3]triazolo[4,5- d ]pyrimidine derivatives as potent USP28 inhibitors. Especially, compound 19 potently inhibited USP28 (IC 50 = 1.10 ± 0.02 μmol/L, K d = 40 nmol/L), showing selectivity over USP7 and LSD1 (IC 50 > 100 μmol/L). Compound 19 was cellularly engaged to USP28 in gastric cancer cells. Compound 19 reversibly bound to USP28 and directly affected its protein levels, thus inhibiting the proliferation, cell cycle at S phase, and epithelial-mesenchymal transition (EMT) progression in gastric cancer cell lines. Docking studies were performed to rationalize the potency of compound 19 . Collectively, compound 19 could serve as a new tool compound for the development of new USP28 inhibitors for exploring the roles of deubiquitinase in cancers.

Alternative approaches to target Myc for cancer treatment

“…Among these derivatives, one compound not only showed high potency and selectivity on the inhibition of USP28 but also suppressed the colony formation, cell proliferation, cell cycle at S phase, migration, and the EMT process in gastric cancer cell lines. 56 S-Phase kinase-associated protein 2. S-Phase kinase-associated protein 2 (Skp2), another ubiquitin ligase F-box protein identified for Myc but different from Fbw7, promotes Myc transcriptional activity through its E3 ubiquitin ligase activity, acting as a transcriptional coactivator.…”

Antiproliferative Activity and Potential Mechanism of Marine-Sourced Streptoglutarimide H against Lung Cancer Cells

“…Benzylaminoethanols (AZ1–AZ4) were the first reported compounds to directly and effectively target USP28 [ 29 ]. More recently, a few synthesized USP28 inhibitors were also reported [ 30 , 31 ]. To the best of our knowledge, streptoglutarimide H is the first USP28 inhibitor found from natural resource to display potent antiproliferative activity against lung cancer cells with unique mechanism of action.…”

Targeting ubiquitin signaling for cancer immunotherapy

“…Small molecule inhibitors for several DUBs have also been developed, and some of them have been shown to inhibit tumor growth in animal models. [220][221][222][223] The most extensively explored DUB for drug development is USP7 with a large number of small molecule inhibitors being developed. 224 In addition to its wellknown function in mediating deubiquitination and stabilization of MDM2, 222 USP7 stabilizes Foxp3 and a histone acetyl transferase, Tip60, thereby maintaining the function of Treg cells in the immune system.…”