Sulfonyl-morpholino-pyrimidines: SAR and development of a novel class of selective mTOR kinase inhibitor

Recent development of ATP-competitive small molecule phosphatidylinostitol-3-kinase inhibitors as anticancer agents

“…In 2012, Finlay et al (AstraZeneca) [55] described a high throughput screening approach to identify ATP competitive mTOR kinase inhibitors, starting with a modestly potent inhibitor sulfonyl morpholinopyrimidine 110 (mTOR IC 50 = 1.41 µM, PI3Kα IC 50 = 17.3 µM). Variation of substituents at the pyrimidine 2, 4, 6 position (111) provided compounds with higher mTOR potency (mTOR IC 50 = 0.02-100 µM, PI3Kα IC 50 = 0.56-300 µM).…”

Targeted Regulation of PI3K/Akt/mTOR/NF-κB Signaling by Indole Compounds and their Derivatives: Mechanistic Details and Biological Implications for Cancer Therapy

“…Though being developed as a competitive inhibitor of the ATP-binding site of Chk2, indole 8 also inhibits mutant AKT1(S473D) at a low concentration (IC 50 = 10.9 nM) and revealed synergistic effects together with topotecan, camptothecin and radiation, while protecting mouse thymocytes from radiation damage. Finlay and co-workers have recently disclosed an indole modified sulfonylmorpholinopyrimidine compound 9 [103]. Indole 9 exhibited selective mTOR inhibiton (IC50 0.288 µM).…”

Pyrrolopyrimidine: A Versatile Scaffold for Construction of Targeted Anti-cancer Agents

“…47 Guided by structure-based design, a series of mTOR selective N-7 substituted imidazolopyrimidines were evaluated and synthesized, the SAR was expanded to include N-Mepyrrolopyrimidine and N-Me-pyrazolopyrimidine scaffolds and these similar ring systems have been reported as potent PI3K and/or mTOR inhibitors [48][49][50][51][52] .…”