On April 12, 2022 Schrödinger, Inc. (Nasdaq: SDGR), whose physics-based software platform is transforming the way therapeutics and materials are discovered, reported that new preclinical data from its Wee1 inhibitor program in a poster session at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting taking place in New Orleans (Press release, Schrodinger, APR 12, 2022, View Source [SID1234612084]). Schrödinger has identified multiple, highly selective and structurally distinct Wee1 inhibitors with optimized physicochemical properties that show strong pharmacodynamic responses and anti-tumor activity in preclinical models. The data presented show that Schrödinger’s Wee1 inhibitors have therapeutic potential for use as monotherapy and as part of combination therapy with other agents.
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"The strength of our data underscore the potential of our novel, orally available and potent Wee1 inhibitors and provide an opportunity to advance a potential best-in-class Wee1 inhibitor into the clinic," said Karen Akinsanya, Ph.D., president of R&D, therapeutics, at Schrödinger. "The differentiated and balanced profile of our Wee1 molecules highlights the impact of our computational platform when deployed at scale to overcome design challenges, such as selectivity and ADME optimization. Our unique lead series were identified by assessing more than 445 million potential compounds computationally with only 42 that were synthesized for further analysis."
Wee1 is a gatekeeper checkpoint kinase that prevents cellular progression through the cell cycle, allowing time for DNA repair before cell division takes place. Inhibition of Wee1 allows for accumulation of DNA damage, triggering DNA breakage and apoptosis in tumor cells. Wee1 is emerging as a potentially important therapeutic target for a range of solid tumors, including ovarian and uterine cancer.
Schrödinger is on track to select a Wee1 development candidate later this year. Subject to completion of the preclinical data packages, Schrödinger anticipates submitting an Investigation New Drug (IND) Application to the U.S. Food and Drug Administration (FDA) in 2023.
Additional Details About the Study
The presentation, "Discovery of potent, selective, and orally available Wee1 inhibitors that demonstrate increased DNA damage and mitosis in tumor cells leading to tumor regression in vivo," highlighted preclinical data with multiple lead compounds discovered using Schrödinger’s proprietary physics-based free energy perturbation (FEP+) modeling technology. These molecules demonstrate superior kinase selectivity compared to other known Wee1 inhibitors in a broad kinase panel. In multiple preclinical models, a representative compound, STC-8123, was well tolerated and demonstrated sustained pharmacodynamic and pharmacokinetic properties. The anti-tumor effects of STC-8123 were maintained during dosing holidays while allowing full recovery of mechanism-based hematological effects, likely due to its sustained plasma concentrations and high exposure in tumors. Schrödinger’s advanced Wee1 program compounds maintained potency, selectivity and anti-tumor activity with no detectable time-dependent inhibition of CYP3A4, a key liver enzyme. Taken together, these data support a profile that may enable a favorable dosing regimen and further evaluation of a potential best-in-class Wee1 inhibitor as both monotherapy and as part of combination therapy with other agents.