ADVANCING A PROMISING AML CANDIDATE: SYNTHESIS SCALE-UP AND IN VIVO EVALUATION OF MEDS433

Human Dihydroorotate Dehydrogenase (hDHODH) is a validated drug target involved in cancer cell metabolism, playing a key role in the de novo pyrimidine biosynthesis pathway. Its inhibition has been identified as a promising strategy to induce cellular differentiation, particularly in Acute Myeloid Leukaemia (AML), where pyrimidine starvation leads to leukemic cell differentiation and apoptosis [1]. Drug Discovery and Clinic (DDC) s.r.l. has developed a novel class of hDHODH inhibitors based on the 2-hydroxypyrazolo[1,5-a]pyridine scaffold, with MEDS433 emerging as a potent pro-apoptotic agent in several AML cell lines [2]. MEDS433 exhibits high enzymatic potency (hDHODH IC50 = 1.2 nM), comparable to other inhibitors currently in clinical trials, which translates into strong cellular effects, making it a promising candidate for preclinical development. To advance MEDS433 toward clinical application, we focused on optimizing its synthetic route, not only to facilitate a seamless transition to clinical trials but also to enable large-scale production to support a comprehensive in vivo characterization. As a result, we have successfully developed a scalable and more sustainable multi-gram synthesis of MEDS433, enabling the generation of promising in vivo efficacy, pharmacokinetic, and toxicity data. These significant advancements have enabled the compound’s transition into the early drug development phase in collaboration with an international CRO, marking a crucial step toward its clinical advancement.