1. Academic Validation
  2. AD80, a multikinase inhibitor, exhibits antineoplastic effects in acute leukemia cellular models targeting the PI3K/STMN1 axis

AD80, a multikinase inhibitor, exhibits antineoplastic effects in acute leukemia cellular models targeting the PI3K/STMN1 axis

  • Invest New Drugs. 2021 Aug;39(4):1139-1149. doi: 10.1007/s10637-021-01066-w.
Jorge Antonio Elias Godoy Carlos 1 Keli Lima 1 Leticia Veras Costa-Lotufo 1 Andrei Leitão 2 João Agostinho Machado-Neto 3
Affiliations

Affiliations

  • 1 Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, CEP 05508-900, São Paulo, SP, Brazil.
  • 2 Medicinal & Biological Chemistry Group, Institute of Chemistry of São Carlos, University of São Paulo, São Paulo, Brazil.
  • 3 Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, CEP 05508-900, São Paulo, SP, Brazil. [email protected].
Abstract

Despite the great advances in the understanding of the molecular basis of acute leukemia, very little of this knowledge has been translated into new therapies. Stathmin 1 (STMN1), a phosphoprotein that regulates microtubules dynamics, is highly expressed in acute leukemia cells and promotes cell cycle progression and proliferation. GDP366 has been described as a STMN1 and Survivin Inhibitor in solid tumors. This study identified structural GDP366 analogs and the cellular and molecular mechanisms underlying their suppressive effects on acute leukemia cellular models. STMN1 mRNA levels were higher in AML and ALL patients, independent of risk stratification (all p < 0.001). Cheminformatics analysis identified three structural GDP366 analogs, with AD80 more potent and effective than GSK2606414 and GW768505A. In acute leukemia cells, GDP366 and AD80 reduced cell viability and autonomous clonal growth in a dose- and/or time-dependent manner (p < 0.05) and induced Apoptosis and cell cycle arrest (p < 0.05). At the molecular level, GDP366 and AD80 reduced Ki-67 (a proliferation marker) expression and S6 ribosomal protein (a PI3K/Akt/mTOR effector) phosphorylation, and induced PARP1 (an Apoptosis marker) cleavage and γH2AX (a DNA damage marker) expression. GDP366 induced STMN1 phosphorylation and Survivin expression, while AD80 reduced Survivin and STMN1 expression. GDP366 and AD80 modulated 18 of the 84 Cytoskeleton regulators-related genes. These results indicated that GDP366 and AD80 reduced the PI3K/STMN1 axis and had cytotoxic effects in acute leukemia cellular models. Our findings further highlight STMN1-mediated signaling as a putative Anticancer target for acute leukemia.

Keywords

AD80; Acute leukemia; GDP366; STMN1; Targeted therapy.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-U00177
    99.67%, Survivin and Op18 Inhibitor