Abstract 5778: RCZY-690: A tri-complex molecular glue pan-RAS (ON) inhibitor exhibiting best-in-class potential for RAS-addicted solid tumors

Abstract The RAS family, including HRAS, KRAS, and NRAS, acts as a master molecular switch that regulates essential cellular processes, including cell growth, proliferation, survival, and differentiation, and is strongly implicated in cancer. As members of the small GTPase superfamily, RAS proteins cycle between an active (GTP-bound) state and an inactive (GDP-bound) state to control key signaling pathways such as the MAPK/ERK and PI3K/AKT. Oncogenic RAS mutations— mostly occur at codons 12, 13, and 61—impair intrinsic or GAP-stimulated GTP hydrolysis, and shifting the equilibrium toward the active, GTP-bound form of RAS. This persistent activation leads to constitutive downstream signaling, driving uncontrolled cell proliferation, enhanced survival, and tumorigenesis. RCZY-690 is a highly potent, orally bioavailable tri-complex molecular glue pan-RAS (ON) inhibitor with Best-in-Class potential. It specifically targets both mutant and wild-type RAS proteins in their active GTP-bound (ON) state, thereby blocking RAS engagement with downstream effectors and disrupting oncogenic signal transduction. In multiple RAS-mutant cell lines, RCZY-690 exhibited significantly greater inhibition of cell proliferation and more profound suppression of downstream p-ERK levels compared with RMC-6236. RCZY-690 has favorable ADME and PK properties, achieving higher exposure, an extended half-life (T1/2), and a flat Cmax/Ctrough concentration-time profile consistent with an improved therapeutic index (TI). Compared to RMC-6236 and ERAS-0015, it shows higher degree of preferential tumor distribution in mouse models. These advantages enable RCZY-690 to achieve comparable tumor growth inhibition (TGI) at doses as low as 1/25th to 1/250th those of RMC-6236 and 1/3rd to 1/10th those of ERAS-0015 across KRAS-mutant CDX and syngeneic tumor mouse models. RCZY-690 demonstrates favorable PK/PD profiles, including more durable DUSP6 suppression than RMC-6236, alongside excellent in vivo tolerability and promising safety margins in preclinical toxicity studies. Taken together, these attributes position RCZY-690 as a promising pan-RAS(ON) inhibitor and support its advancement toward an Investigational New Drug (IND) filing planned for Q2 2026. Citation Format: Xiaojing (Celia) Chen, Lin Wang, Xiaohong Liu, Qiaoni You, Shenjun Li, Ling Wang, Shanshan Bi, Jing Jiang, Jianming Bao. RCZY-690: A tri-complex molecular glue pan-RAS (ON) inhibitor exhibiting best-in-class potential for RAS-addicted solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5778.