Senior Director Modeling & Simualtion Nimbus Therapeutics Lexington, Massachusetts, United States
Disclosure(s):
zhenhong Li: No financial relationships to disclose
Objectives: Werner syndrome helicase (WRN) is a promising synthetic lethal drug target for cancer patients with microsatellite instability high (MSI-H) tumors [1]. Covalent [2] and non-covalent [3] WRN inhibitors have now been described, and both have entered clinical development for the treatment of MSI-H tumors. However, the relative advantages of these two modes of action remain unknown. To address this question, we developed mechanistic PK/PD (pharmacokinetic/pharmacodynamic) models to study the similarities and differences between the two modes of action using an in-silico experimentation approach.
Methods: The models were coded in R. For non-covalent inhibitors, the PD model included the reversible binding process between WRN and inhibitors, as well as the synthesis, natural degradation, and induced degradation rates of WRN protein [3]. For covalent inhibitors, the PD model was structurally similar, but the reversible binding was replaced with irreversible binding, and the inactivation of WRN protein was added [2]. Both PD models were parameterized using either measured (e.g., kon, koff) or published values (e.g., WRN half-life [3]). To simulate in vitro studies, inhibitor concentrations were assumed to be constants. To simulate in vivo studies, compartmental PK models were integrated with the PD models. The PKPD models were then used to simulate WRN engagement by covalent and non-covalent inhibitors at the observed efficacious concentrations in vitro, and efficacious doses in mouse xenograft models in vivo [2,3]. Sensitivity of WRN engagement to each model parameter was analyzed by scanning a range of values of each model parameter (i.e., 10-fold higher and lower of the default values).
Results: The analysis results of these PKPD models suggest that optimization of kon helps to increase the potency of both covalent and non-covalent inhibitors. However, when kon values are comparable, covalent inhibitors of WRN have limited advantages over non-covalent inhibitors, especially when the plasma half-life of a non-covalent inhibitor is long and WRN protein resynthesis rate is low.
Conclusions: The modeling framework concludes that well-optimized non-covalent WRN inhibitors can match the target engagement of covalent inhibitors, while offering potential safety advantages from their transient, tunable binding.
Citations: [1] Kategaya et al. Werner Syndrome Helicase Is Required for the Survival of Cancer Cells with Microsatellite Instability. iScience, Volume 13, 488 – 497 (2019) [2] Baltgalvis et al. Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase. Nature 629, 435–442 (2024). [3] Ferretti et al. Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers. Nature 629, 443–449 (2024).
