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

Abstract

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.

Human VDAC pseudogenes: an emerging role for VDAC1P8 pseudogene in acute myeloid leukemia

“…In light of the expression data of the VDAC1 gene and its pseudogene VDAC1P8 retrieved from public repository, we decided to experimentally evaluate their expression in 5 different acute myeloid leukemia cell lines. Exactly, we tested HL60, OCI-AML/2 and OCI-AML/3 (as myelocytic AML cell lines), MOLM13 (as monocytic AML cell line) and IMS-M2 (as megakaryocytic AML cell line) [ 55 – 57 ].…”

Computer-Aided Identification of Kinase-Targeted Small Molecules for Cancer: A Review on AKT Protein

“…In 2022, three computer-aided drug discovery (CADD) approaches described the identification of new competitive AKT1 small molecule inhibitors endowed with anti-cancer activities [ 20 , 25 , 26 ].…”

“…Finally, we have recently reported the identification of novel competitive AKT1 inhibitors as possible agents against acute myeloid leukemia (AML) [ 20 ]. The serendipitous discovery of compound 12 ( Figure 6 ) as an AKT1 inhibitor prompted us to carry out modeling studies to aid the selection of 12 -like compounds for biological testing.…”

“…Following our interest in the kinase inhibitors’ field [ 18 , 19 ], we recently investigated the AKT1, reporting the identification of a novel ATP-site-directed AKT1 inhibitor with anticancer activity [ 20 ]. Even though, to date, no FDA-approved drugs against this protein are on the market, many efforts have been made in the discovery of molecules capable of targeting AKT by binding to one of its three pockets [ 4 , 13 , 21 ], with particular emphasis on small molecules for cancer treatment [ 3 , 4 , 14 ].…”