Siremadlin (NVP-HDM201), a compound belonging to the imidazolopyrrolidinone class, demonstrates a promising in vivo profile and has recently progressed to Phase 1 clinical trials targeting cancer patients^[2].

In Arf−/− mice, constitutive PiggyBac (PB) mutagenesis generates a spectrum of spontaneous tumors with well-documented insertional mutations. These tumors, when allografted into larger mouse cohorts, serve as models for evaluating the therapeutic impact of Siremadlin (NVP-HDM201). Out of 21 allograft models tested, 16 exhibit sensitivity to Siremadlin (NVP-HDM201), although treatment resistance eventually develops. Analyzing both Siremadlin (NVP-HDM201)-resistant and untreated tumors highlights 87 genes uniquely affected by PB transposon insertions, revealing insights into resistance mechanisms^[1].

The administration of Siremadlin (NVP-HDM201), through either a continuous low-dose daily schedule or a single high-dose approach, distinctly modulates the p53 pathway. Unlike the continual low-dose regimen, a single high-dose of Siremadlin (NVP-HDM201) triggers a significant and immediate increase in p53-dependent PUMA expression and apoptosis. This effect correlates with substantial and enduring tumor shrinkage observed following a high-dose of Siremadlin (NVP-HDM201), regardless of whether it's given orally or via injection. Comparative efficacy and safety of these dosing strategies are under investigation in an ongoing clinical trial, aiming to determine the optimal regimen based on long-term outcomes and tolerability^[3].

Siremadlin (NVP-HDM201) interrupts the interaction between TP53 and MDM2 in both human and mouse cells, exhibiting nanomolar IC50 values and effectively preventing TP53 degradation^[1].