WYE-687

Last updated
WYE-687
WYE-687 structure.png
Identifiers
  • methyl N-[4-[4-morpholin-4-yl-1-[1-(pyridin-3-ylmethyl)piperidin-4-yl]pyrazolo[3,4-d]pyrimidin-6-yl]phenyl]carbamate
CAS Number
PubChem CID
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C28H32N8O3
Molar mass 528.617 g·mol−1
3D model (JSmol)
  • COC(=O)NC1=CC=C(C=C1)C2=NC3=C(C=NN3C4CCN(CC4)CC5=CN=CC=C5)C(=N2)N6CCOCC6
  • InChI=1S/C28H32N8O3/c1-38-28(37)31-22-6-4-21(5-7-22)25-32-26(35-13-15-39-16-14-35)24-18-30-36(27(24)33-25)23-8-11-34(12-9-23)19-20-3-2-10-29-17-20/h2-7,10,17-18,23H,8-9,11-16,19H2,1H3,(H,31,37)
  • Key:VDOCQQKGPJENHJ-UHFFFAOYSA-N

WYE-687 is a drug which acts as an inhibitor of both subtypes of the mechanistic target of rapamycin (mTOR), mTORC1 and mTORC2. It is being researched for potential applications in the treatment of various forms of cancer. [1] [2] [3]

Related Research Articles

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Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration.

mTOR Mammalian protein found in Homo sapiens

The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene. mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases.

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<span class="mw-page-title-main">RHEB</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">P70-S6 Kinase 1</span> Protein-coding gene in the species Homo sapiens

Ribosomal protein S6 kinase beta-1 (S6K1), also known as p70S6 kinase, is an enzyme that in humans is encoded by the RPS6KB1 gene. It is a serine/threonine kinase that acts downstream of PIP3 and phosphoinositide-dependent kinase-1 in the PI3 kinase pathway. As the name suggests, its target substrate is the S6 ribosomal protein. Phosphorylation of S6 induces protein synthesis at the ribosome.

<span class="mw-page-title-main">RPTOR</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">PI3K/AKT/mTOR pathway</span> Cell cycle regulation pathway

The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. Therefore, it is directly related to cellular quiescence, proliferation, cancer, and longevity. PI3K activation phosphorylates and activates AKT, localizing it in the plasma membrane. AKT can have a number of downstream effects such as activating CREB, inhibiting p27, localizing FOXO in the cytoplasm, activating PtdIns-3ps, and activating mTOR which can affect transcription of p70 or 4EBP1. There are many known factors that enhance the PI3K/AKT pathway including EGF, shh, IGF-1, insulin, and CaM. Both leptin and insulin recruit PI3K signalling for metabolic regulation. The pathway is antagonized by various factors including PTEN, GSK3B, and HB9.

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mTOR inhibitors Class of pharmaceutical drugs

mTOR inhibitors are a class of drugs that inhibit the mechanistic target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs). mTOR regulates cellular metabolism, growth, and proliferation by forming and signaling through two protein complexes, mTORC1 and mTORC2. The most established mTOR inhibitors are so-called rapalogs, which have shown tumor responses in clinical trials against various tumor types.

mTORC1 Protein complex

mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.

mTOR Complex 2 (mTORC2) is an acutely rapamycin-insensitive protein complex formed by serine/threonine kinase mTOR that regulates cell proliferation and survival, cell migration and cytoskeletal remodeling. The complex itself is rather large, consisting of seven protein subunits. The catalytic mTOR subunit, DEP domain containing mTOR-interacting protein (DEPTOR), mammalian lethal with sec-13 protein 8, and TTI1/TEL2 complex are shared by both mTORC2 and mTORC1. Rapamycin-insensitive companion of mTOR (RICTOR), mammalian stress-activated protein kinase interacting protein 1 (mSIN1), and protein observed with rictor 1 and 2 (Protor1/2) can only be found in mTORC2. Rictor has been shown to be the scaffold protein for substrate binding to mTORC2.

<span class="mw-page-title-main">David M. Sabatini</span> American scientist who co-discovered mTOR

David M. Sabatini is an American scientist and a former professor of biology at the Massachusetts Institute of Technology. From 2002 to 2021, he was a member of the Whitehead Institute for Biomedical Research. He was also an investigator of the Howard Hughes Medical Institute from 2008 to 2021 and was elected to the National Academy of Sciences in 2016. He is known for his contributions in the areas of cell signaling and cancer metabolism, most notably the co-discovery of mTOR.

<span class="mw-page-title-main">Michael N. Hall</span> American-Swiss molecular biologist

Michael Nip Hall is an American-Swiss molecular biologist and professor at the Biozentrum of the University of Basel, Switzerland. He discovered TOR, a protein central for regulating cell growth.

<span class="mw-page-title-main">XL-388</span> Chemical compound

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<span class="mw-page-title-main">Torin-1</span>

Torin-1 is a drug which was one of the first non-rapalog derived inhibitors of the mechanistic target of rapamycin (mTOR) subtypes mTORC1 and mTORC2. In animal studies it has anti-inflammatory, anti-cancer, and anti-aging properties, and shows activity against neuropathic pain.

References

  1. Yu K, Toral-Barza L, Shi C, Zhang WG, Lucas J, Shor B, et al. (August 2009). "Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin". Cancer Research. 69 (15): 6232–40. doi: 10.1158/0008-5472.CAN-09-0299 . PMID   19584280.
  2. Cheng F, Wang L, Shen Y, Xia J, Chen H, Jiang Y, Lu M (February 2016). "Preclinical evaluation of WYE-687, a mTOR kinase inhibitor, as a potential anti-acute myeloid leukemia agent". Biochemical and Biophysical Research Communications. 470 (2): 324–330. doi:10.1016/j.bbrc.2016.01.054. PMID   26792718.
  3. Pan XD, Gu DH, Mao JH, Zhu H, Chen X, Zheng B, Shan Y (2017). "Concurrent inhibition of mTORC1 and mTORC2 by WYE-687 inhibits renal cell carcinoma cell growth in vitro and in vivo". PLOS ONE. 12 (3): e0172555. Bibcode:2017PLoSO..1272555P. doi: 10.1371/journal.pone.0172555 . PMC   5336203 . PMID   28257457.