Targeted protein degradation (TPD) is an emerging therapeutic strategy that would benefit from new chemical entities with which to recruit a wider variety of ubiquitin E3 ligases to target proteins for proteasomal degradation. Here we describe a TPD strategy involving the recruitment of FBXO22 to induce degradation of the histone methyltransferase and oncogene NSD2. UNC8732 facilitates FBXO22-mediated degradation of NSD2 in acute lymphoblastic leukemia cells harboring the NSD2 gain-of-function mutation p.E1099K, resulting in growth suppression, apoptosis and reversal of drug resistance. The primary amine of UNC8732 is metabolized to an aldehyde species, which engages C326 of FBXO22 to recruit the SCF^FBXO22 Cullin complex. We further demonstrate that a previously reported alkyl amine-containing degrader targeting XIAP is similarly dependent on SCF^FBXO22. Overall, we present a potent NSD2 degrader for the exploration of NSD2 disease phenotypes and a new FBXO22-recruitment strategy for TPD.

靶向蛋白质降解 (TPD) 是一种新兴的治疗策略，它将受益于新的化学实体，通过新的化学实体招募更广泛的泛素 E3 连接酶来靶向蛋白质以进行蛋白酶体降解。在这里，我们描述了一种 TPD 策略，涉及招募 FBXO22 来诱导组蛋白甲基转移酶和癌基因 NSD2 的降解。 UNC8732 促进带有 NSD2 功能获得性突变 p.E1099K 的急性淋巴细胞白血病细胞中 FBXO22 介导的 NSD2 降解，从而导致生长抑制、细胞凋亡和耐药性逆转。 UNC8732 的伯胺代谢为醛类，该醛类与 FBXO22 的 C326 结合以招募 SCF ^FBXO22 Cullin 复合物。我们进一步证明，先前报道的针对 XIAP 的含烷基胺降解剂同样依赖于 SCF ^FBXO22 。总体而言，我们提出了一种用于探索 NSD2 疾病表型的有效 NSD2 降解剂，以及一种针对 TPD 的新 FBXO22 招募策略。