α‑Aminoboronic Acid Moieties in Boro Dipeptides Modulate Proteasome Subunit Selectivity and Provide Access to Compounds with Potent Anticancer and Anti-Inflammatory Activity

Proteasomes regulate cellular protein homeostasis and
are key targets
in treating cancer, inflammation, and autoimmune diseases. The two
main forms, the constitutive proteasome and immunoproteasome, each
contain three catalytically active subunits with distinct substrate
specificities. The first approved proteasome inhibitor, bortezomib,
is nonselective and causes dose-limiting toxicity. Herein, we report
dipeptide boronic acids with varying P1 residues, prepared using our
recently developed method for α-aminoboronic acids formation.
Most compounds inhibited various immuno/proteasome subunits in the
low nanomolar range, displaying inhibition profiles distinct from
bortezomib, ranging from β5i/β1i-selective to β5c/β5i-directed
inhibitors. Although their cytotoxicity to cancer cells was not improved
compared to bortezomib, selected compounds proved less toxic to noncancer
cells and with anti-inflammatory activity comparable to that of zetomipzomib
(KZR-616). The presented boro dipeptides with tailored P1 residues
provide a basis for designing subunit-selective compounds with boronic
acid as the warhead and optimized P2 and/or P3 positions.

蛋白酶体（Proteasome）可调控细胞蛋白质稳态，是治疗癌症、炎症及自身免疫性疾病的关键靶点。目前已知的两类主要蛋白酶体形式分别为组成型蛋白酶体（constitutive proteasome）与免疫蛋白酶体（immunoproteasome），二者均含有3个具备独特底物特异性的催化活性亚基。首款获批的蛋白酶体抑制剂硼替佐米（bortezomib）缺乏选择性，且会引发剂量限制性毒性。
本研究报道了一系列带有不同P1残基的二肽硼酸类化合物，通过我们近期开发的α-氨基硼酸合成方法制备得到。
多数化合物可在低纳摩尔浓度范围内抑制多种免疫/蛋白酶体亚基，其抑制谱与硼替佐米截然不同，覆盖从β5i/β1i选择性抑制剂到靶向β5c/β5i的抑制剂区间。
尽管此类化合物对肿瘤细胞的细胞毒性未优于硼替佐米，但部分筛选得到的化合物对非肿瘤细胞的毒性更低，且抗炎活性可与泽托米佐米（zetomipzomib，KZR-616）相媲美。
本研究开发的带有定制化P1残基的硼酰二肽类化合物，为设计以硼酸为药效弹头、且P2和/或P3位点经过优化的亚基选择性抑制剂奠定了研究基础。