5-(4-aMino-1-isopropyl-1H-pyrazolo[3,4-d]pyriMidin-3-yl)benzo[d]oxazol-2-aMine

Description

INK128 is an inhibitor of TORC1/2, acting as an ATP-dependent inhibitor of mTOR kinase (IC₅₀ = 1 nM). It blocks the phosphorylation of downstream substrates of both TORC1 and TORC2. INK128 interferes with the growth of cell lines which are resistant to rapamycin and pan-PI3K inhibitors. Moreover, daily, oral administration of INK128 inhibits angiogenesis and tumor growth in several xenograft models. The effects of INK128 on gene expression also reduce invasion and metastasis.

Uses

3-(2-Amino-5-benzoxazolyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine is a potent and selective TORC1/2 inhibitor with broad oral antitumor activity. TORC1/2 inhibitors are mechanistically distinct from rapamycinand offer a compelling approach to the treatment of cancer by targeting translational control, cell metabolism, growth andangiogenesis.

Definition

ChEBI: 5-(4-amino-1-propan-2-yl-3-pyrazolo[3,4-d]pyrimidinyl)-1,3-benzoxazol-2-amine is a benzoxazole.

Biological Activity

Sapanisertib (MLN0128, INK 128, TAK-228) is a potent and selective mTOR inhibitor with IC50 of 1 nM in cell-free assays; >200-fold less potent to class I PI3K isoforms, superior in blocking mTORC1/2 and sensitive to pro-invasion genes (vs Rapamycin). Phase 1.

in vitro

INK 128 exhibits an enzymatic inhibition activity against mTOR and more than 100-fold selectivity to PI3K kinases. As TORC1/2 inhibitor, INK 128 inhibits both the phosphorylation of S6 and 4EBP1, the downstream substrates of TORC1, and selectively inhibits AKT phosphorylation at Ser473, the downstream substrate of TORC2. Furthermore, INK 128 also shows potent inhibition effects on cell lines resistant to rapamycin and pan-PI3K inhibitors.

in vivo

In a ZR-75-1 breast cancer xenograft model, INK 128 shows tumor growth inhibition efficacy at a dose of 0.3 mg/kg/day. Daily, oral administration of INK 128 inhibits angiogenesis and tumor growth in multiplexenograft models.

target

mTOR

References

1) Hsieh?et al.?(2012),?The translational landscape of mTOR signaling steers cancer initiation and metastasis; Nature,?485?55 2) Gokmen-Polar?et al.?(2012)?Investigational drug MLN0128, a novel TORC1/2 inhibitor, demonstrates potent oral antitumor activity in human breast cancer xenograft models; Breast Cancer Res. Treat.,?136?673