PO.MCB03.01 · 分子与细胞生物学
SPR2015是一种高效且选择性的KRAS G12D（ON）抑制剂，在临床前模型中作为单药对结直肠癌表现出良好的药代动力学特性和显著的抗肿瘤疗效
SPR2015, a highly potent and selective KRAS G12D (on) inhibitor, exhibits favorable pharmacokinetic behavior and significant anti-tumor efficacy against colorectal cancer as monotherapy in preclinical models
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摘要 Abstract
中文摘要
结直肠癌（CRC）是全球第三大常见恶性肿瘤和第二大癌症相关死亡原因。迄今为止，CRC的有效治疗手段仍然有限。约40%的结直肠癌患者携带KRAS突变，其中KRAS G12D突变占比最大。尽管目前有许多KRAS G12D（OFF或ON）选择性抑制剂处于临床开发中，其中若干在胰腺导管腺癌（PDAC）和非小细胞肺癌（NSCLC）患者中报告了有前景的临床结果，但作为单药，尚无一种在CRC患者中显示出具有临床意义的疗效。SPR2015是一种高效且选择性的KRAS G12D（ON）抑制剂，在多种KRAS G12D细胞系中具有纳摩尔级的增殖抑制活性，同时对KRAS野生型具有良好的选择性。共晶结构显示，SPR2015通过与亲环蛋白A（CypA）紧密结合并与G12D形成共价键，从而形成三元复合物。SPR2015在人和小鼠CypA结合实验中均表现出更长的CypA停留时间和改善的靶点结合动力学。在小鼠中口服给药SPR2015——单独或与另一种G12D（ON）抑制剂（盒式PK）联合——明确证实了此类抑制剂的靶点介导药物处置（TMDD）PK行为。SPR2015通过增强CypA竞争性结合，实现快速而持续的靶点结合，优于另一种G12D（ON）抑制剂。在小鼠PDAC/NSCLC异种移植模型中，SPR2015在10 mg/kg（口服，q.d.）时有效抑制肿瘤生长，并在30 mg/kg（口服，q.d.）时实现肿瘤消退。这些模型中的伴随PK/PD研究建立了肿瘤生长抑制疗效、下游对DUSP6 mRNA的PD抑制，以及血液、肿瘤和其他组织中药物暴露之间的相关性。此外，在超过15个CRC细胞衍生异种移植（CDX）或患者来源异种移植（PDX）模型中，以单剂量100 mg/kg（口服，q.d.）评估了SPR2015与另一种G12D（ON）抑制剂的小鼠头对头临床试验。SPR2015在这些体内CRC异种移植模型中显示出显著优越的疗效，作为单药实现了64.7%的客观缓解率（ORR）和94.1%的疾病控制率（DCR）。在安全性方面，SPR2015表现出良好的体外安全性特征，并在28天啮齿动物重复给药毒理学研究中耐受性良好。SPR2015目前正处于IND申报支持阶段，预计将于2026年底推进至人体1期研究。
查看英文原文 English abstract
Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related deaths worldwide. To date, effective treatments for CRC remain limited. About 40% of colorectal patients harbor KRAS mutations, with KRAS G12D mutation accounting for the largest population. Although many KRAS G12D (off or on) selective inhibitors are currently in clinical development, with several reported promising clinical results in pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) patients, none have demonstrated clinically meaningful efficacy in CRC patients as monotherapy. SPR2015 is a highly potent and selective KRAS G12D (on) inhibitor with nanomolar proliferation inhibitory activities in various KRAS G12D cell lines while with good selectivity over KRAS wild type. Co-crystal structure showed that SPR2015 formed tri-complexes via binding tightly with cyclophilin A (CypA) and forming a covalent bond with G12D. SPR2015 exhibited longer CypA residence time and improved target engagement kinetics in both human and mouse CypA binding assays. Oral administration of SPR2015 in mice-alone or together with another G12D (on) inhibitor (cassette PK) - clearly confirmed target-mediated drug disposition (TMDD) PK behaviors of this type inhibitors. SPR2015 outperformed the other G12D (on) inhibitor achieving rapid and sustain target engagement via enhanced CypA competitive binding. In mouse PDAC/NSCLC xenograft models, SPR2015 effectively inhibited tumor growth at 10 mg/kg (oral, q.d.) and achieved tumor regression at 30 mg/kg (oral, q.d.). Accompanying PK/PD studies in these models established the correlation between tumor growth inhibition efficacy, downstream PD inhibition on DUSP6 mRNA, and drug exposures in blood, tumor, and other tissues. Furthermore, a mouse head-to-head clinical trial was evaluated between SPR2015 and another G12D (on) inhibitor in over 15 CRC cell-derived xenograft (CDX) or patient-derived xenograft (PDX) models, using a single dose at 100 mg/kg (oral, q.d.). SPR2015 showed significantly superior efficacy in these in vivo CRC xenograft models, achieving a 64.7% objective response rate (ORR) and 94.1% disease control rate (DCR) as monotherapy. On the safety part, SPR2015 demonstrated favorable in vitro safety profiles and was well-tolerated in a 28-day rodent repeat dosing tox studies. SPR2015 is currently under IND-enabling and is expected to advance to human Phase 1 study by the end of 2026.
利益披露 Disclosure
Y. Qian, None..
Z. Zhang, None..
Z. Fu, None..
K. Zhou, None..
M. Dai, None..
S. Liu, None..
Y. Zhang, None..
T. Hu, None.