PDF(Pubmed)
Abstract：
\"Undruggable\" targets such as KRAS are particularly challenging in the development of drugs. We devised a novel chemical knockdown strategy, CANDDY (Chemical knockdown with Affinity aNd Degradation DYnamics) technology, which promotes protein degradation using small molecules (CANDDY molecules) that are conjugated to a degradation tag (CANDDY tag) modified from proteasome inhibitors. We demonstrated that CANDDY tags allowed for direct proteasomal target degradation independent of ubiquitination. We synthesized a KRAS-degrading CANDDY molecule, TUS-007, which induced degradation in KRAS mutants (G12D and G12V) and wild-type KRAS. We confirmed the tumor suppression effect of TUS-007 in subcutaneous xenograft models of human colon cells (KRAS G12V) with intraperitoneal administrations and in orthotopic xenograft models of human pancreatic cells (KRAS G12D) with oral administrations. Thus, CANDDY technology has the potential to therapeutically target previously undruggable proteins, providing a simpler and more practical drug targeting approach and avoiding the difficulties in matchmaking between the E3 enzyme and the target.
摘要：
像KRAS这样的“不可用”目标在药物开发中尤其具有挑战性。我们设计了一种新颖的化学击倒策略，CANDDY（具有亲和力的化学击倒Nd降解动力学）技术，其使用与从蛋白酶体抑制剂修饰的降解标签(CANDDY标签)缀合的小分子(CANDDY分子)促进蛋白质降解。我们证明了CANDDY标签允许直接蛋白酶体靶标降解而不依赖于泛素化。我们合成了一种KRAS降解CANDDY分子，TUS-007,其在KRAS突变体(G12D和G12V)和野生型KRAS中诱导降解。我们证实了TUS-007在腹膜内给药的人结肠细胞皮下异种移植模型（KRASG12V）和口服给药的人胰腺细胞原位异种移植模型（KRASG12D）中的肿瘤抑制作用。因此，CANDDY技术有可能在治疗上靶向以前不可用的蛋白质，提供了一种更简单、更实用的药物靶向方法，并避免了E3酶与靶标匹配的困难。
