PBI-381，一种针对KRasG12D实体瘤的开发候选PROTAC

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, Pro teolysis Ta rgeting C himera (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 DC 50 (degradation IC 50 ) < 1 nM and D max (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.