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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2023-01, Vol.28 (3), p.1224
• Main Authors: Ghelli Luserna di Rorà, Andrea, Jandoubi, Mouna, Martinelli, Giovanni, Simonetti, Giorgia
• Format: Article
• Language: English
• Subjects: Acute Disease; Acute lymphoblastic leukemia; Acute myeloid leukemia; Adaptor Proteins, Signal Transducing - metabolism; Analysis; Animal models; Animals; Apoptosis; Binding sites; Bioavailability; Biocompatibility; Blast cells; Care and treatment; Cell Cycle; Cell Cycle Proteins - metabolism; Cell Division; Cell growth; Cell Line, Tumor; Cell Proliferation; CHK1 protein; Depolymerization; Diagnosis; DNA damage; DNA-Binding Proteins - metabolism; FLT3; Humans; Inhibitors; Kinases; Leukemia; Leukemia, Myeloid, Acute - metabolism; Lymphatic leukemia; Mice; Mutation; novel compounds; Nuclear Proteins - metabolism; p53 Protein; Physiology; proliferation; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proteins; Review; Stat5 protein; Therapeutic applications; Therapeutic targets; Toxicity; Transcription Factors - metabolism; Tumor proteins; Xenografts; Xenotransplantation
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules28031224

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, PI3Kδ, 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.