1.Project Profile

(1) Asset type: PROTAC

(2)Indications: Solid tumor

(3) Dosage form and administration: Intravenous injection, once weekly

(4) Research phase: IND enabling

(5) Cooperation demands: License-out

2.Strategy of design

KRAS mutations are common in a variety of cancers
Although KRAS inhibitors that are selective for KRAS^G12Cand KRAS^G12D have been identified and are currently in clinical studies, treatment options for other KRAS mutation-driven cancers and KRAS^WT-ampcancers are lacking.
Advantagesof pan-KRAS drugs
Broad patient population
Cancers driven by KRAS WT (e.g., KRAS amplified)
Feasibility for undrugged mutants
Heterogenous cancers driven by multiple KRAS aberrations
Overcome on-target KRAS resistance to allele-specific inhibitors
Small molecular pan-KRAS inhibitors are only effective against KRAS mutant tumors, no effect on WT tumors
Pan-KRAS PROTAC degraders could targetmultiple KRAS mutants, and achieve strong degradation activity and long-lasting in vivo PD effect

3.Highlights

Asset shows time- and dose-dependent KRAS degradation and antiproliferative effects in multiple KRAS mutant and WT variants
Asset has a stronger binding affinity toward KRAS over NRAS or HRAS
Asset shows comparable potency to BI compound Patent (ACBI3) in KRAS-WT amplification cell lines

Asset achieves tumor regression with weekly dosing in KRAS WT and mutant models.