Larkspur Biosciences has announced the discovery of LRK-4189, a first-in-class degrader of the lipid kinase PIP4K2C designed to treat microsatellite stable (MSS) colorectal cancer and other solid tumors. The Cambridge-based company presented its breakthrough at the prestigious MEDI First Time Disclosures session at the American Chemical Society Fall 2025 meeting in Washington, DC.
Novel Mechanism Targets Cancer Cell Fitness
LRK-4189 represents a paradigm shift in cancer therapy by targeting cancer cell fitness rather than traditional oncogenic pathways. The drug selectively degrades phosphatidylinositol 5-phosphate 4-kinase, type II, gamma (PIP4K2C), a lipid kinase that cancer cells co-opt to enhance their survival by evading immune surveillance and adapting to stress conditions.
"Genetic studies have long highlighted PIP4K2C as a key player in cancer stress adaptation, but its extremely low kinase activity made it resistant to conventional inhibition approaches," said Catherine Sabatos-Peyton, PhD, CEO of Larkspur Biosciences. "With our novel degrader, LRK-4189, we've finally unlocked this critical pathway."
Promising Preclinical Efficacy Data
LRK-4189 demonstrates subnanomolar potency in primary human cells as an orally bioavailable, selective degrader. The drug's mechanism involves degrading PIP4K2C to induce intrinsic cancer cell death while activating interferon signaling, creating multiple killing mechanisms specifically effective against difficult-to-treat MSS colorectal cancer cells.
In vivo studies revealed dose-dependent pharmacokinetic and pharmacodynamic properties, with single-agent efficacy across multiple colorectal cancer models. The drug also demonstrated synergy when combined with first-line standard-of-care chemotherapy regimens.
Superior Performance in Patient-Derived Models
In primary human colorectal cancer patient-derived spheroids, LRK-4189 achieved a 50% response rate with preferential activity in MSS colorectal cancer. This performance compares favorably to cetuximab, which achieved a 35% response rate in the same testing platform. Cetuximab serves as either first- or second-line treatment for patients with RAS wild-type colorectal cancer.
Addressing Significant Unmet Medical Need
The therapeutic target addresses a substantial patient population, as microsatellite stable colorectal cancer accounts for approximately 85% of the 150,000 colorectal cancer cases diagnosed annually in the United States, according to the American Cancer Society. PIP4K2C is associated with poor outcomes across multiple cancer types, including colorectal and breast cancers.
Clinical Development Timeline
LRK-4189 has completed IND-enabling studies and is positioned to initiate a Phase 1 clinical trial in the fourth quarter of 2025. The drug's mechanism of reducing cancer cell fitness, triggering intrinsic apoptosis, and engaging immune system clearance of residual tumor cells positions it to potentially overcome limitations of existing therapies.
Company Platform and Leadership
Larkspur Biosciences utilizes its proprietary LarkX bioinformatics platform, which combines machine learning with tumor genetics to identify cancer cell fitness pathways and develop clinical strategies for potential responders across multiple cancer types. The company's scientific founders include Lewis C. Cantley, PhD, from Dana-Farber Cancer Institute and Harvard Medical School; Vijay K. Kuchroo, DVM, PhD, from Harvard Medical School and Brigham and Women's Hospital; and Nathanael Gray, PhD, from Stanford University.
