PP242

PP242 Property

Melting point:

>187°C (dec.)

Boiling point:

642.0±50.0 °C(Predicted)

Density 

1.55

Flash point:

342.097℃

storage temp. 

-20°C Freezer, Under inert atmosphere

solubility 

DMSO (Slightly), Methanol (Slightly, Sonicated)

form 

White powder solid.

pka

9.51±0.40(Predicted)

color 

Pale Brown to Light Brown

Safety

HS Code 

29339900

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H315Causes skin irritation

H319Causes serious eye irritation

H335May cause respiratory irritation

Precautionary statements

P261Avoid breathing dust/fume/gas/mist/vapours/spray.

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

P271Use only outdoors or in a well-ventilated area.

P280Wear protective gloves/protective clothing/eye protection/face protection.

P302+P352IF ON SKIN: wash with plenty of soap and water.

P304+P340IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

P312Call a POISON CENTER or doctor/physician if you feel unwell.

P321Specific treatment (see … on this label).

P332+P313IF SKIN irritation occurs: Get medical advice/attention.

P337+P313IF eye irritation persists: Get medical advice/attention.

P362Take off contaminated clothing and wash before reuse.

P403+P233Store in a well-ventilated place. Keep container tightly closed.

P405Store locked up.

P501Dispose of contents/container to..…

PP242 Chemical Properties,Usage,Production

Description

The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that is central to two protein complexes, mTORC1 and mTORC2. These complexes are differentially regulated (e.g., only mTORC1 is sensitive to rapamycin) and regulate different pathways. PP242 is an inhibitor of the active site of mTOR kinase in both mTORC1 and mTORC2 (IC₅₀ = 8 nM). It less effectively inhibits PKCα, PI3-kinase subunit p110γ, JAK2, PKCβI, and PKCβII (IC₅₀ = 49, 102, 110, 198, and 185, respectively). PP242 has been shown to cause the death of certain human and murine leukemia cells more potently than rapamycin and, in vivo, delays leukemia onset and augments the effects of tyrosine kinase inhibitors in suppressing leukemic expansion and extending survival.

Uses

PP 242 is used in leukemia therapy suppressing mTOR signaling. Dual mTORC1/C2 inhibitor.

Definition

ChEBI: A member of the class of pyrazolopyrimidines that is 1H-pyrazolo[3,4-d]pyrimidine substituted by isopropyl, 5-hydroxyindol-2-yl and amino groups at positions 1, 3 and 4 respectively. It is a potent inhibitor of mTOR and exhi its anti-cancer properties.

Enzyme inhibitor

This ATP-competitive mTORC1/mTORC2 inhibitor (FW = 308.34 g/mol; CAS 1092351-67-1; Solubility: 25 mM in DMSO), also named 2-[4-amino- 1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-1H-indol-5-ol, has a IC50 = 8 nM for both isoforms of mammalian target of rapamycin (mTOR), also known as FK506-binding protein 12-rapamycin-associated protein 1, or FRAP1, a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription. PP-242 shows considerable selectivity for mTOR versus PI3K family kinases. In models of acute leukemia harboring the Philadelphia chromosome (Ph) translocation, PP242, but not rapamycin, causes death of mouse and human leukemia cells. Indeed, PP242 completely inhibits TORC1 and TORC2 signaling in BCR-ABL+ cells, whereas rapamycin partially suppresses TORC1 and drives a PI3K/AKT surge. Moreover, PP242 augments TNF-related apoptosis-inducing ligand- (TRAIL-) induced apoptosis in NSCLC cells, indicating that mTORC2 regulates Cbl-dependent FLIPS degradation and TRAIL-induced apoptosis Other Targets: p110γ (IC50 = 0.102 μM); DNA-PK ((IC50 = 0.408 μM); p110δ ((IC50 = 1.27 μM); p110α ((IC50 = 1.96 μM), and p110β ((IC50 = 2.2 μM), with much weaker inhibition of 215 other kinases.

storage

Store at +4°C

References

[1] BETH APSEL. Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases[J]. Nature chemical biology, 2008, 4 11: 691-699. DOI: 10.1038/nchembio.117
[2] MORRIS E FELDMAN. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2.[J]. PLoS Biology, 2009, 7 2: e38. DOI: 10.1371/journal.pbio.1000038
[3] FUMIAKI KOJIMA . Prostaglandin E2 activates Rap1 via EP2/EP4 receptors and cAMP-signaling in rheumatoid synovial fibroblasts: Involvement of Epac1 and PKA[J]. Prostaglandins & other lipid mediators, 2009, 89 1: Pages 26-33. DOI: 10.1016/j.prostaglandins.2009.03.001
[4] MATTHEW R JANES. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor[J]. Nature Medicine, 2010, 16 2: 205-213. DOI: 10.1038/nm.2091