SOS1 is an essential guanine nucleotide exchange factor for RAS that also plays a critical role in the activation of the small GTPase RAC mediated by BCR-ABL in leukemogenesis. Despite this, small molecule inhibitors targeting SOS1 have shown limited efficacy in clinical trials for KRAS mutant cancers, and their potential as a therapeutic approach for chronic myeloid leukemia (CML) remains largely unexplored. In this study, we developed a potent SOS1 PROTAC SIAIS562055, which was designed by connecting a CRBN ligand to an analogue of the SOS1 inhibitor BI-3406. SIAIS562055 exhibited sustained degradation of SOS1 and inhibition of downstream ERK pathways, resulting in superior anti-proliferative activity compared to small molecule inhibitors. SIAIS562055 also potentiated the activity of both KRAS inhibitors in KRAS-mutant cancers and ABL inhibitors in BCR-ABL+ CML. In KRAS-mutant xenografts, SIAIS562055 displayed promising antitumor potency as a monotherapy and enhanced ERK inhibition and tumor regression when combined with KRAS inhibitors, overcoming acquired resistance. In CML cells, SIAIS562055 promoted the active uptake of BCR-ABL inhibitors by upregulating the carnitine/organic cation transporter SLC22A4. SIAIS562055 and BCR-ABL inhibitors synergistically enhanced inhibition of ABL phosphorylation and downstream signaling, demonstrating robust antitumor activities in both mouse xenografts and primary CML patient samples. In summary, this study suggests that PROTAC-mediated SOS1 degradation represents an effective therapeutic strategy for treating not only KRAS-mutant cancers but also BCR-ABL-harboring leukemia.

中文翻译：

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SOS1 的靶向降解表现出强大的抗癌活性，并克服了 KRAS 突变肿瘤和 BCR-ABL 阳性白血病的耐药性


SOS1 是 RAS 必需的鸟嘌呤核苷酸交换因子，在 BCR-ABL 介导的白血病发生中小 GTP 酶 RAC 的激活中也起关键作用。尽管如此，靶向 SOS1 的小分子抑制剂在 KRAS 突变癌症的临床试验中显示出有限的疗效，并且它们作为慢性粒细胞白血病 （CML） 治疗方法的潜力在很大程度上仍未得到探索。在这项研究中，我们开发了一种有效的 SOS1 PROTAC SIAIS562055，它是通过将 CRBN 配体连接到 SOS1 抑制剂 BI-3406 的类似物来设计的。SIAIS562055表现出 SOS1 的持续降解和下游 ERK 通路的抑制，与小分子抑制剂相比，具有更强的抗增殖活性。SIAIS562055 还增强了 KRAS 突变癌症中 KRAS 抑制剂和 BCR-ABL+ CML 中 ABL 抑制剂的活性。在 KRAS 突变异种移植物中，SIAIS562055 作为单一疗法显示出有希望的抗肿瘤效力，当与 KRAS 抑制剂联合使用时，增强了 ERK 抑制和肿瘤消退，克服了获得性耐药。在 CML 细胞中，SIAIS562055 通过上调肉碱/有机阳离子转运蛋白SLC22A4促进 BCR-ABL 抑制剂的活性摄取。SIAIS562055 和 BCR-ABL 抑制剂协同增强对 ABL 磷酸化和下游信号传导的抑制，在小鼠异种移植物和原发性 CML 患者样本中均表现出强大的抗肿瘤活性。总之，这项研究表明，PROTAC 介导的 SOS1 降解代表了一种有效的治疗策略，不仅可以治疗 KRAS 突变癌症，还可以治疗携带 BCR-ABL 的白血病。