Demonstrating intracellular protein target engagement is an essential step in the development and progression of new chemical probes and potential small molecule therapeutics. However, this can be particularly challenging for poorly studied and noncatalytic proteins, as robust proximal biomarkers are rarely known. To confirm that our recently discovered chemical probe 1 (CCT251236) binds the putative transcription factor regulator pirin in living cells, we developed a heterobifunctional protein degradation probe. Focusing on linker design and physicochemical properties, we generated a highly active probe 16 (CCT367766) in only three iterations, validating our efficient strategy for degradation probe design against nonvalidated protein targets.

中文翻译：

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使用 Pirin 蛋白降解探针 (CCT367766) 演示细胞内靶标接合。

证明细胞内蛋白质靶标参与是新化学探针和潜在小分子疗法开发和进步的重要一步。然而，这对于研究不足的非催化蛋白质尤其具有挑战性，因为很少有人知道强大的近端生物标志物。为了证实我们最近发现的化学探针 1 (CCT251236) 与活细胞中推定的转录因子调节剂 pirin 结合，我们开发了一种异双功能蛋白质降解探针。专注于接头设计和物理化学特性，我们仅在 3 次迭代中生成了一个高活性探针 16 (CCT367766)，验证了我们针对未经验证的蛋白质靶标进行降解探针设计的有效策略。