RT Journal Article
T1 From Serendipity to Rational Identification of the 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one Core as a New Chemotype of AKT1 Inhibitors for Acute Myeloid Leukemia
A1 Astolfi, Andrea
A1 Milano, Francesca
A1 Palazzotti, Deborah
A1 Brea, Jose
A1 Pismataro, Maria Chiara
A1 Morlando, Mariangela
A1 Tabarrini, Oriana
A1 Loza García, María Isabel
A1 Massari, Serena
A1 Martelli, Maria Paola
A1 Barreca, Maria Letizia
K1 AKT1
K1 kinase inhibitors
K1 cancer
K1 acute myeloid leukemia
K1 rare disease
K1 molecular modeling
K1 molecular docking
K1 similarity search
K1 MD simulation
K1 computer-aided drug discovery
AB 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 T187 as an AKT1 inhibitor has paved the way to the rational identification of new active small molecules, among which T126 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-d]pyrimidin-4(3H)-one derivative T126 is worthy of future biological experiments and medicinal chemistry efforts aimed at developing a novel chemical class of AKT1 inhibitors as anti-AML agents.
PB MDPI
SN 1999-4923
YR 2022
FD 2022-10-26
LK https://hdl.handle.net/10347/45300
UL https://hdl.handle.net/10347/45300
LA eng
NO Pharmaceutics 2022, 14(11), 2295; https://doi.org/10.3390/pharmaceutics14112295
DS Minerva
RD 24 abr 2026