From Serendipity to Rational Identification of the 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-<i>d</i>]pyrimidin-4(3<i>H</i>)-one Core as a New Chemotype of AKT1 Inhibitors for Acute Myeloid Leukemia

• Main Authors: Andrea Astolfi (Author), Francesca Milano (Author), Deborah Palazzotti (Author), Jose Brea (Author), Maria Chiara Pismataro (Author), Mariangela Morlando (Author), Oriana Tabarrini (Author), Maria Isabel Loza (Author), Serena Massari (Author), Maria Paola Martelli (Author), Maria Letizia Barreca (Author)
• Format: Book
• Published: MDPI AG, 2022-10-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy whose prognosis is globally poor. In more than 60% of AML patients, the PI3K/AKTs/mTOR signaling pathway is aberrantly activated because of oncogenic driver alterations and further enhanced by chemotherapy as a mechanism of drug resistance. Against this backdrop, very recently we have started a multidisciplinary research project focused on AKT1 as a pharmacological target to identify novel anti-AML agents. Indeed, the serendipitous finding of the in-house compound <b>T187</b> as an AKT1 inhibitor has paved the way to the rational identification of new active small molecules, among which <b>T126</b> has emerged as the most interesting compound with IC₅₀ = 1.99 ± 0.11 μM, ligand efficiency of 0.35, and a clear effect at low micromolar concentrations on growth inhibition and induction of apoptosis in AML cells. The collected results together with preliminary SAR data strongly indicate that the 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-<i>d</i>]pyrimidin-4(3<i>H</i>)-one derivative <b>T126</b> is worthy of future biological experiments and medicinal chemistry efforts aimed at developing a novel chemical class of AKT1 inhibitors as anti-AML agents.

Item Description

10.3390/pharmaceutics14112295
1999-4923