Abstract 7279: Discovery of SHR1127, an orally bioavailable, highly potent and selective KRAS G12D inhibitor
Authors: Li Xin , Shen Feng , Zhang Limin , Wang Wei , Kong Luyao , Bao Yong , Mao Yuchang , Wang Zaiyong , Lin Sophie , Zhang Zhe , Feng Jun , Hu Min , He Feng 
Published: March 2024

Mutant KRAS is the most frequent oncogenic driver in nearly 23% of human cancers. As the most common KRAS alteration, KRAS G12D mutation occurs in approximately 35%, 13%, and 4% of pancreatic, colorectal, and non-small cell lung cancers, respectively. It was worth noting that the clinical PoC of KRAS G12D inhibitor has been preliminarily validated by intravenous administration of HRS-4642 weekly. However, there still represents an extraordinary unmet clinical need requiring an oral KRAS G12D inhibitor featuring higher potency and favorable pharmacokinetic profiles. We disclose herein the development of an orally bioavailable, highly potent and selective KRAS G12D inhibitor, SHR1127.SHR1127 demonstrated picomolar binding affinity, with a KD value of 0.06 nM in a SPR binding assay with GDP-loaded KRAS G12D protein. SHR1127 significantly inhibited ERK phosphorylation with IC50s of 0.05 nM and 0.19 nM in GP2d and AGS cell lines, respectively. More importantly, 3D viability assay showed that SHR1127 displayed extremely high anti-proliferative activity against GP2d, AGS and AsPC-1 cell lines with the IC50s of 0.05, 0.83 and 0.92 nM, respectively. The selectivity over KRAS WT PC9 cells, KRAS G12C and G12V mutant cell lines was more than 500-fold. Additionally, SHR1127 displayed excellent human hepatocyte stability (T1/2 &gt; 1000 min) and desirable physicochemical properties. Moreover, SHR1127 exhibited favorable pharmacokinetic profiles with dose-dependent exposure and acceptable oral bioavailability. In the GP2d xenograft model, SHR1127 showed a robust anti-tumor activity in a dose-dependent manner, leading to tumor regression (TGI = 125%) as low as 5 mg/kg (p.o. dosage, bid), without body-weight loss during 21 days of treatment. Furthermore, SHR1127 demonstrated no off-target activities at 1000 nM in 97 kinase panel and 78 safety panel screening. SHR1127 showed good safety window in the 14-day toxicology study in rat and dog.

In summary, SHR1127 has been successfully developed as an orally bioavailable KRAS G12D inhibitor, exhibiting excellent cellular activities with good selectivity over KRAS WT. More importantly, SHR1127 showed favorable pharmacokinetic profiles across species, and robust tumor regression in a GP2d xenograft model at the dose of 5 mg/kg. In addition, SHR1127 demonstrated no off-target toxicity and good safety window. An IND submission for SHR1127 is planned in the first half of 2024.

Citation Format: Xin Li, Feng Shen, Limin Zhang, Wei Wang, Luyao Kong, Yong Bao, Yuchang Mao, Zaiyong Wang, Sophie Lin, Zhe Zhang, Jun Feng, Min Hu, Feng He. Discovery of SHR1127, an orally bioavailable, highly potent and selective KRAS G12D inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7279.