ATP-Competitive Inhibitors of the Mammalian Target of Rapamycin: Design and Synthesis of Highly Potent and Selective Pyrazolopyrimidines

Abstract

The mammalian target of rapamycin (mTOR), a central regulator of growth, survival, and metabolism, is a validated target for cancer therapy. Rapamycin and its analogues, allosteric inhibitors of mTOR, only partially inhibit one mTOR protein complex. ATP-competitive, global inhibitors of mTOR that have the potential for enhanced anticancer efficacy are described. Structural features leading to potency and selectivity were identified and refined leading to compounds with in vivo efficacy in tumor xenograft models.

Ligand-based 3-D pharmacophore generation and molecular docking of mTOR kinase inhibitors

“…The C-terminal region of mTOR (residues 1330-2549) is homologous to PI3Kγ (NCBI accession ID: NP_002640.2). The kinase domain region of mTOR (2145-2446) was modeled based on the crystal structure of PI3γ kinase bound to a pyrazolopyrimidine inhibitor (PDB_ID: 3IBE) as a template [21]. The template and mTOR sequences were aligned using CLUSTALW [22].…”

“…Another inhibitor of mTOR, Ku-0063794, has been shown to have high specificity for mTOR compared to other lipid kinases [19]. Nowak et al and Zask et al modeled the structure of mTOR based on the crystal structure of PI3γ kinase in order to study the binding modes of inhibitors [20,21]. Nowak et al used highthroughput screening to identify mTOR inhibitors that, upon optimization, yielded selective mTOR inhibitors with high affinity compared to PI3α kinase.…”

Conformational Selection versus Induced Fit in Kinases: The Case of PI3K‐γ

“…These structures showed a significant conformational variability in the binding cavity. [18][19][20] This variability is particularly prominent in the oncogenic target PI3K-g, which makes it a valid and interesting system with which to explore conformational selection versus the induced-fit hypothesis (Figure 1; see also Figures S1 and S2 in the Supporting Information).…”

Synthesis and Biological Evaluation of N- Pyrazolyl Derivatives and Pyrazolopyrimidine Bearing a Biologically Active Sulfonamide Moiety as Potential Antimicrobial Agent

“…Also, the pyrazolo [4,3-d]pyrimidinone class of compounds is very important in the treatment of impotence [16], used as an PDE5 inhibitor. PP30 possesses a good kinase selectivity profile used as ATP-competitive mTORC1/mTORC2 inhibitors [17,18] (Figure 1). In view of these observations and as a continuation of our previous work on heterocyclic chemistry, we report herein the synthesis of some new heterocyclic-containing pyrazolo [3,2-d]pyrimidine moieties and the study of their antimicrobial activities in comparison to Cefotaxime and miconazole as reference drugs.…”