Abstract 4593: PBI-381, a development candidate PROTAC for KRasG12D solid tumors

Abstract Kras gain-of-function mutations are prominent cancer drivers in pancreatic, colorectal, lung and other solid tumors. While several small molecule inhibitors against KRasG12C have been approved to treat non-small cell lung and colorectal cancers, either as single agent or in combination, there is still a great unmet need for other more prevalent Kras mutations such as KrasG12D. Furthermore, given the complexity of KRasG12D molecular mode of action and its downstream signaling branches, whether complete elimination of the KRasG12D protein or functional inhibition of its signaling activity has a bigger impact on cancer cells remains an open question. Therefore, Proteolysis Targeting Chimera (PROTAC)-based Kras degraders may bring differentiated clinical benefits to patients with Kras-mutant solid tumors. At present, ASP3082 (Astellas Pharma) and PT0253 (PAQ Therapeutics) are the only two KRasG12D PROTAC degraders that have entered clinical trials. Polymed Biopharmaceuticals has generated a series of potent and selective PROTAC molecules targeting the KRasG12D mutant protein. In vitro, these PROTAC molecules exhibited DC50 (degradation IC50) < 1 nM and Dmax (maximal % of degradation) > 98% against KRasG12D in cancer cell lines harboring this mutation. Moreover, as measured by cancer cell growth inhibition, the Polymed PROTAC molecules are highly selective against cells with the KRasG12D mutation while sparing cells harboring KRasG12V, KRasG12C or cells with amplified wild type KRas. More importantly, in KRasG12D pancreatic cancer xenograft model PK59, treatment with the lead molecule PBI-381 resulted in robust tumor regression without impact on body weight and any other noticeable adverse effects on the mice after 4 weeks of treatment. A good PK/PD/efficacy relationship was also observed with PBI-381. Preliminary ADME, in vitro safety and drug-drug interaction assessments further supported PBI-381 as a development candidate for advancing into the clinic. Compared to the most clinically advanced KRasG12D PROTAC ASP3082, PBI-381 has superior potency and more favorable tissue distribution for a drug designed to treat solid tumors. In head-to-head comparison studies using xenograft models, PBI-381 also exhibited significantly higher anti-tumor activity than ASP3082. IND-enabling activities on PBI-381 are underway to progress the compound further towards the clinic. Citation Format: Bing Zhang, Yuxin Liu, Yufeng Chen, Danqiu Lin, Jinhua Chai, Yang Meng, Mixue Tong, Ganng Yang, Michael Xiang, Liping Zhao, Rui Yang, Lan Xu, He Zhou, Jason Xiang. PBI-381, a development candidate PROTAC for KRasG12D 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 4593.