RMC-6236

RMC-6236 is a reversible, GTP-binding RAS (ON) multi-selective inhibitor. RMC-6236 inhibits the active, GTP-bound state of both mutant and wild-type canonical RAS isoforms and has broad therapeutic potential in cancers driven by the RAS signaling pathway. RMC-6236 acts by forming a ternary complex: it first binds cyclophilin A (CypA; Kd=55.3nM) to form a binary complex, which then associates with RAS proteins, including KRAS (wild-type, G12V, and G12D), with Kd values of 131, 364, and 154nM, respectively^[1][2].

In vitro, RMC-6236 significantly inhibits the growth of RAS-mutant cancer cell lines harboring KRAS G12X and NRAS Q61X mutations, with EC₅₀ values of 8 and 22nM, respectively^[2]. Treatment of GP2D colorectal cancer cells with 10nM RMC-6236 for 4-48 hours did not sustain suppression of mTOR pathway activity, whereas combination with KO-2806 prevented its rebound^[3].

In vivo, a single oral gavage dose of RMC-6236 at 10 or 25mg/kg reduced tumor Dual Specificity Phosphatase 6 (DUSP6) levels by more than 95% at 8 hours and maintained more than 90% inhibition at 24 hours; at 25mg/kg, it also sustained more than 80% inhibition of pERK levels at 24 hours post-dose in mouse xenograft models^[2]. RMC-6236 administered orally at 10-25mg/kg once daily for 4 weeks showed dose-dependent antitumor activity in KRAS-mutant human tumor xenograft models, including Capan-2, NCI-H441, HPAC, and NCI-H358^[2]. RMC-6236, administered orally at 25mg/kg once daily for 28 days, inhibited tumor growth in xenograft models of KRAS^G12C-mutant NCI-H2122 non-small cell lung cancer and KRAS^G12D-mutant GP2D colorectal cancer^[3].

References:
[1] Long SA, Amparo AM, Goodhart G, Ahmad SA, Waters AM. Evaluation of KRAS inhibitor-directed therapies for pancreatic cancer treatment. Front Oncol. 2024;14:1402128.
[2] Jiang J, Jiang L, Maldonato BJ, et al. Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers. Cancer Discov. 2024;14(6):994-1017.
[3] Patel H V, et al. The farnesyl transferase inhibitor KO-2806 re-sensitizes relapsing tumors to RAS inhibition. BioRxiv, 2024: 2024.12. 20.629824.

RMC-6236是一种可逆的，GTP结合的RAS（ON）多选择性抑制剂。RMC-6236能够抑制包括突变型和野生型在内的经典RAS亚型的活性（GTP结合）状态，并在由RAS信号通路驱动的癌症中具有广泛的治疗潜力。RMC-6236通过形成三元复合物发挥作用：其首先与环孢素蛋白A（CypA；Kd=55.3nM）结合形成二元复合物，随后与RAS蛋白结合，包括KRAS（野生型、G12V和G12D），其对应的Kd分别为131、364和154nM^[1][2]。

体外实验中，RMC-6236能显著抑制RAS突变癌细胞系KRASG12X和NRASQ61X的生长，其EC₅₀值分别为8和22nM^[2]。用10nM的RMC-6236处理GP2D结直肠癌细胞4-48小时，未能持续抑制mTOR通路活性，而与KO-2806联合使用则可防止其活性反弹^[3]。

体内实验中，在小鼠异种移植模型中，单次口服灌胃给予10或25mg/kg的RMC-6236，可在给药后8小时使肿瘤中双特异性磷酸酶（DUSP6）水平降低超过95%，并在24小时仍维持超过90%的抑制作用；在25mg/kg剂量下，其在给药后24 小时仍可维持超过 80%的pERK 水平抑制作用^[2]。RMC-6236以10-25mg/kg剂量口服灌胃给药，每日一次，连续4周，在携带常见KRAS突变的人源肿瘤异种移植模型中（包括Capan-2、NCI-H441、HPAC和NCI-H358）均表现出剂量依赖性的抗肿瘤活性^[2]。RMC-6236以25mg/kg剂量口服给药，每日一次，连续28天，在KRAS^G12C 突变的NCI-H2122非小细胞肺癌和KRAS^G12D突变的GP2D结直肠癌异种移植模型中抑制了肿瘤生长^[3]。