PO.ET07.01 · 实验与分子治疗
SP09253，一种口服生物利用度高、高效力的RAS(ON)分子胶抑制剂，在KRAS突变肿瘤中展示出强大的抗肿瘤活性
SP09253, an orally bioavailable, highly potent RAS(ON) molecular glue inhibitor demonstrates robust anti-tumor activity in KRAS-mutant tumors
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摘要 Abstract
中文摘要
KRAS是最常发生突变的癌症驱动基因。约30%的人类肿瘤携带KRAS突变，在胰腺癌、结直肠癌和非小细胞肺癌（NSCLC）等中患病率尤其高。携带KRAS突变的患者对当前临床治疗药物常表现出疗效差和低反应。尽管KRAS G12C突变选择性抑制剂在治疗G12C突变患者方面已取得成功，但超过85%的其他“不可成药”KRAS突变仍缺乏有效的治疗选择。靶向多种致癌RAS变体同时保留野生型RAS的下一代KRAS抑制剂具有解决更广泛适应症和患者群体的潜力。SP09253是一种口服生物利用度高、高效力的泛RAS分子胶抑制剂，对包括KRAS G12C、G12D、G12V、G13D在内的关键RAS突变展示出强大的活性，同时对野生型KRAS表现出高选择性。重要的是，与阳性对照相比，SP09253表现出更有利的ADME和PK特征，且SP09253的体内抗肿瘤疗效优于阳性对照——一种目前正在进行III期临床试验的同类首创泛RAS分子胶。SP09253是一种强效的泛RAS分子胶，已被证明可选择性抑制KRAS突变体但保留野生型KRAS。SP09253在体外强效抑制KRAS突变型细胞系中的ERK磷酸化和细胞活力。SP09253在携带不同突变类型（包括G12C、G12D、G12V等）的KRAS突变型异种移植中展示出强大的体内疗效，同时展现出有利的PK特征和口服生物利用度。
查看英文原文 English abstract
KRAS is the most frequently mutated cancer driver gene. Approximately 30% of human tumors harbor KRAS mutations, with particularly high prevalence in pancreatic, colorectal, and non-small cell lung cancers (NSCLC), among others. Patients carrying KRAS mutations often exhibit poor efficacy and low response to current clinical therapeutics. Although KRAS G12C mutant-selective inhibitors have shown success in treating patients with G12C mutations, more than 85% of other “undruggable” KRAS mutations still lack effective treatment options. Next-generation KRAS inhibitors that target multiple oncogenic RAS variants while sparing wild-type RAS hold the potential to address broader indications and patient population. SP09253 is an orally bioavailable, highly potent pan-RAS molecular glue inhibitor that demonstrates robust activity against key RAS mutations including KRAS G12C, G12D, G12V, G13D, while exhibiting high selectivity over wild-type KRAS. Importantly, SP09253 exhibits more favorable ADME and PK profiles compared to positive control, and the in vivo anti-tumor efficacy of SP09253 is superior to that of a positive control, a first-in-class pan-RAS molecular glue currently undergoing Phase III clinical trial.SP09253 is a potent pan-RAS molecular glue that has been proven to selectively inhibits KRAS mutants but spares wild type KRAS. SP09253 potently inhibits ERK phosphorylation and cellular viability in KRAS mutantt cell lines in vitro . SP09253 demonstrates robust in vivo efficacy in KRAS mutant xenografts harboring different mutant types, including G12C, G12D, G12V, etc., while showcasing a favorable PK profile and oral bioavailability.<!--EndFragment-->
利益披露 Disclosure
Z. Zhang,
Hefei Shengpu Pharmaceutical Employment.
X. Di,
Hefei Shengpu Pharmaceutical Co., Ltd. g., Board of Directors, non-salaried role).
Q. Sun,
Hefei Shengpu Pharmaceutical Co., Ltd. g., Board of Directors, non-salaried role).