Modeling of cell cycle response to cyclin-dependent kinase 12 (CDK12) inhibition

Background: In vitro studies have shown that CDK12 inhibition (CDK12i) leads to DNA damage accumulation, cell cycle arrest, and mitotic defects which result in antiproliferation. modeling translation vivo can elucidate the PK-PD-efficacy relationship of CDK12i subsequently simulate efficacy new dosing regimens. The goal this work was develop a mechanistic model describe effect on proliferation using H1048 cells, translate predict tumor growth (TGI) an CDX (Cell Line-Derived Xenograft) model. Methods: Total count, Brdu staining, Annexin-V/ PI staining data used antiproliferation, apoptosis, respectively. Model development decisions were made goodness-of-fit criteria, with focus bias minimization physiological plausibility. translated ratio vehicle arm DMSO treated rates as scaling factor. vitro-in predictions compared observed TGI data. Results: best fitting four compartment ordinary differential equations It consisted three compartments loop: G0/G1, from cells go into S, G2/M. From G2/M, re-entered reflecting division upon mitosis. Cells could fourth (apoptosis) S or Two drug effects included: Emax-effect rate constant G2/M representing out death chosen structure based fit probability transition apoptosis each phase constants not known priori. EC50 values estimated be 11 nM for G2 arrest Emax 1900 is close antiproliferative compound while much higher than any clinically relevant dose, suggesting causes antiproliferation primarily through arrest. Finally, closely predicted captured holidays. Conclusions: We developed describing it TGI. final suggests enter able impact drug-holidays, alternative No conflict interest.