2. Academic Validation
  3. Development of Epigenetic Modifiers with Therapeutic Potential in FMS-Related Tyrosine Kinase 3/Internal Tandem Duplication (FLT3/ITD) Acute Myeloid Leukemia and Other Blood Malignancies

Development of Epigenetic Modifiers with Therapeutic Potential in FMS-Related Tyrosine Kinase 3/Internal Tandem Duplication (FLT3/ITD) Acute Myeloid Leukemia and Other Blood Malignancies

  • ACS Pharmacol Transl Sci. 2024 Jul 2;7(7):2125-2142. doi: 10.1021/acsptsci.4c00208.
Gabriele Carullo 1,  Sara Rossi 1,  Valentina Giudice 2,  Alex Pezzotta 3,  Ugo Chianese 4,  Pasqualina Scala 2,  Sabrina Carbone 3,  Anna Fontana 1,  Giovanna Panzeca 1,  Silvia Pasquini 5,  Chiara Contri 6,  Sandra Gemma 1,  Anna Ramunno 7,  Simona Saponara 8,  Francesca Galvani 9,  Alessio Lodola 9,  Marco Mor 9,  Rosaria Benedetti 4 10,  Carmine Selleri 2,  Katia Varani 6,  Stefania Butini 1,  Lucia Altucci 4 10 11,  Fabrizio Vincenzi 6,  Anna Pistocchi 3,  Giuseppe Campiani 1 12
Affiliations

Affiliations

  • 1 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, Siena 53100, Italy.
  • 2 Department of Medicine, Surgery, Dentistry "Scuola Medica Salernitana", University of Salerno, Via S. Allende, Baronissi, SA 84081, Italy.
  • 3 Department of Medical Biotechnology and Translational Medicine, University of Milan, LITA, Fratelli Cervi 93, Segrate, MI 20054, Italy.
  • 4 Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via de Crecchio 7, Naples 80138, Italy.
  • 5 Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Borsari 46, Ferrara 44121, Italy.
  • 6 Department of Translational Medicine, University of Ferrara, Via Borsari 46, Ferrara 44121, Italy.
  • 7 Department of Pharmacy, University of Salerno, Giovanni Paolo II, 132, Fisciano, SA 84084, Italy.
  • 8 Department of Life Sciences, University of Siena, Via Aldo Moro 2, Siena 53100, Italy.
  • 9 Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, Parma 43124, Italy.
  • 10 Program of Medical Epigenetics, Vanvitelli Hospital, Naples 80138, Italy.
  • 11 Biogem Institute of Molecular and Genetic Biology, Ariano Irpino 83031, Italy.
  • 12 Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan 81746-7346, Iran.
PMID: 39022363 DOI: 10.1021/acsptsci.4c00208
Abstract

Blood cancers encompass a group of diseases affecting the blood, bone marrow, or lymphatic system, representing the fourth most commonly diagnosed Cancer worldwide. Leukemias are characterized by the dysregulated proliferation of myeloid and lymphoid cells with different rates of progression (acute or chronic). Among the chronic forms, hairy cell leukemia (HCL) is a rare disease, and no drugs have been approved to date. However, acute myeloid leukemia (AML) is one of the most aggressive malignancies, with a low survival rate, especially in cases with FLT3-ITD mutations. Epigenetic modifications have emerged as promising strategies for the treatment of blood cancers. Epigenetic modulators, such as histone deacetylase (HDAC) inhibitors, are increasingly used for targeted Cancer therapy. New hydroxamic acid derivatives, preferentially inhibiting HDAC6 (5a-q), were developed and their efficacy was investigated in different blood cancers, including multiple myeloma (MM), HCL, and AML, pointing out their pro-apoptotic effect as the mechanism of cell death. Among the inhibitors described, 5c, 5g, and 5h were able to rescue the hematopoietic phenotype in vivo using the FLT3-ITD zebrafish model of AML. 5c (leuxinostat) proved its efficacy in cells from FLT3-ITD AML patients, promoting marked acetylation of α-tubulin compared to histone H3, thereby confirming HDAC6 as a preferential target for this new class of hydroxamic acid derivatives at the tested doses.

Figures
Products