Targeting Proliferation Signals and the Cell Cycle Machinery in Acute Leukemias: Novel Molecules on the Horizon

Abstract

Uncontrolled proliferative signals and cell cycle dysregulation due to genomic or functional alterations are important drivers of the expansion of undifferentiated blast cells in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells. Therefore, they are largely studied as potential therapeutic targets in the field. We here present the most recent advancements in the evaluation of novel compounds targeting cell cycle proteins or oncogenic mechanisms, including those showing an antiproliferative effect in acute leukemia, independently of the identification of a specific target. Several new kinase inhibitors have been synthesized that showed effectiveness in a nanomolar to micromolar concentration range as inhibitors of FLT3 and its mutant forms, a highly attractive therapeutic target due to its driver role in a significant fraction of AML cases. Moreover, we introduce novel molecules functioning as microtubule-depolymerizing or P53-restoring agents, G-quadruplex-stabilizing molecules and CDK2, CHK1, PI3Kd, STAT5, BRD4 and BRPF1 inhibitors. We here discuss their mechanisms of action, including the downstream intracellular changes induced by in vitro treatment, hematopoietic toxicity, in vivo bio-availability and efficacy in murine xenograft models. The promising activity profile demonstrated by some of these candidates deserves further development towards clinical investigation.

AML under the Scope: Current Strategies and Treatment Involving FLT3 Inhibitors and Venetoclax-Based Regimens

“…Given the high frequency of FLT3 mutations in AML and their correlation with poor prognosis, in recent years, extensive research focusing on the development of targeted therapies was conducted, aiming to enhance patient outcomes. Due to these studies, FLT3i can be categorized using two classification systems: first-and second-generation based on their specificity, and Type I and II inhibitors based on their mechanism of action [45,57]. Each FLT3i inhibits receptor autophosphorylation and downstream signaling activation by interacting with the ATP-binding site of the intracellular tyrosine kinase domain.…”

“…The current approach to the treatment of AML with FLT3 mutations includes the use of midostaurin as part of initial chemotherapy, followed by gilteritinib as a stand-alone treatment for relapsed disease [51]. Patients often develop secondary mutations that are responsible for the emergence of resistance to these drugs, including mutations in FLT3 itself [57]. When discussing the mechanisms of resistance that occur, two kinds of resistance should be mentioned: genetic and non-genetic.…”