K252A

K252a is an alkaloid isolated from Nocardiopsis sp. soil fungi. K252A is a highly potent cell permeable CaM Kinase II inhibitor (IC50=1.8nM). At higher concentrations it also inhibits broad spectrum of protein kinases 1–8 . It is an excellent research tool of NGF receptors-trk-signal transduction due to its potent inhibition of trk-NGF receptor-tyrosine kinase activity.

K252a inhibits PKA, PKG, MLCK, PKC, CaMK, phosphorylase kinase, MAP kinase, the trk family of receptor tyrosine kinases and numerous other kinases by acting as a competitive inhibitor with respect to ATP. K252a binds to neuroblastoma membrane with high affinity (2.7 nM). This compound is also observed to promote survival of primary neuronal cultures (75 nM) and to induce neurite outgrowth in SH-SY5Y neuroblastoma cells, an event which is accompanied by enhanced phosphorylation of FAK

K252A is said to be an ATP analog, though I do not really understand why. However its action has to do something with ATP: K252a and CEP1347 are Kinase inhibitors that block ATP binding to target enzymes SOURCE

K252A inhibits at 0.200uM the NGF induced differentiation of pheochromocytoma PC12 cells.

K252a inhibits, at 0.05 uM concentrations, 80% of NGF induced trk-tyrosine Kinase activity.

UV spectrum: 205, 250, 289, 334, 367 nm
Solubility: DMSO, dichloromethane, methanol
Molecular weight: 467.5
Molecular Formula: : C₂₇H₂₁N₃O₅
CAS number: [97161-97-2]

Toxity

Organism	Route	LD50	Source
mouse	intraperitoneal	>300 mg/kg	Journal of Antibiotics. Vol. 38, Pg. 1437, 1985.

References

Raychaudhuri SP, Sanyal M, Weltman H, Kundu-Raychaudhuri S.
K252a, a high-affinity nerve growth factor receptor blocker, improves psoriasis: an in vivo study using the severe combined immunodeficient mouse-human skin model.
J Invest Dermatol. 2004 Mar;122(3):812-9.
Winston JH, Toma H, Shenoy M, He ZJ, Zou L, Xiao SY, Micci MA, Pasricha PJ.
Acute pancreatitis results in referred mechanical hypersensitivity and neuropeptide up-regulation that can be suppressed by the protein kinase inhibitor k252a. J Pain. 2003 Aug;4(6):329-37.
Roux PP, Dorval G, Boudreau M, Angers-Loustau A, Morris SJ, Makkerh J, Barker PA.
K252a and CEP1347 are neuroprotective compounds that inhibit mixed-lineage kinase-3 and induce activation of Akt and ERK.
J Biol Chem. 2002 Dec 20;277(51):49473-80. Epub 2002 Oct 17 Nheu TV, He H, Hirokawa Y, Tamaki K, Florin L,
Schmitz ML, Suzuki-Takahashi I, Jorissen RN, Burgess AW, Nishimura S, Wood J, Maruta H.
The K252a derivatives, inhibitors for the PAK/MLK kinase family selectively block the growth of RAS transformants.
Cancer J. 2002 Jul-Aug;8(4):328-36.
Morotti A, Mila S, Accornero P, Tagliabue E, Ponzetto C.
K252a inhibits the oncogenic properties of Met, the HGF receptor.
Oncogene. 2002 Jul 25;21(32):4885-93.
Hirayama E, Sasao N, Yoshimasu S, Kim J.
K252a, an indrocarbazole derivative, causes the membrane of myoblasts to enter a fusion-capable state.
Biochem Biophys Res Commun. 2001 Aug 3;285(5):1237-43.
Tamaki K, Shotwell JB, White RD, Drutu I, Petsch DT, Nheu TV, He H, Hirokawa Y, Maruta H, Wood JL.
Efficient syntheses of novel C2'-alkylated (+/-)-K252a analogues.
Org Lett. 2001 May 31;3(11):1689-92.
Lee KH, Lee SH, Kim D, Rhee S, Kim C, Chung CH, Kwon H, Kang MS.
Promotion of skeletal muscle differentiation by K252a with tyrosine phosphorylation of focal adhesion: a possible involvement of small GTPase Rho.
Exp Cell Res. 1999 Nov 1;252(2):401-15.
Chin LS, Murray SF, Doherty PF, Singh SK.
K252a induces cell cycle arrest and apoptosis by inhibiting Cdc2 and Cdc25c.
Cancer Invest. 1999;17(6):391-5.
Mohri T, Kameshita I, Suzuki S, Hioki K, Tokunaga R, Takatani S.
Rapid adhesion and spread of non-adherent colon cancer Colo201 cells induced by the protein kinase inhibitors, K252a and KT5720 and suppression of the adhesion by the immunosuppressants FK506 and cyclosporin A.
Cell Struct Funct. 1998 Oct;23(5):255-64.

Local abstracts

1 The Trk tyrosine kinase inhibitor K252a regulates growth of lung adenocarcinomas

2 K252a, an inhibitor of Trk, disturbs pathfinding of hippocampal mossy fibers

3 K252a inhibits proliferation of ovarian cancer cells by upregulating p21WAF1

4 Increasing the kinase specificity of k252a by protein surface recognition.

5 The neuroprotective effects of K252a through inhibiting MLK3/MKK7/JNK3 signaling pathway on ischemic brain injury in rat hippocampal CA1 region.

6 Enhancement of Schwann cell myelin formation by K252a in the Trembler-J mouse dorsal root ganglion explant culture.

7 K252a, a high-affinity nerve growth factor receptor blocker, improves psoriasis: an in vivo study using the severe combined immunodeficient mouse-human skin model.

8 Acute pancreatitis results in referred mechanical hypersensitivity and neuropeptide up-regulation that can be suppressed by the protein kinase inhibitor k252a.

9 K252a and CEP1347 are neuroprotective compounds that inhibit mixed-lineage kinase-3 and induce activation of Akt and ERK.

10 The K252a derivatives, inhibitors for the PAK/MLK kinase family selectively block the growth of RAS transformants.

11 K252a inhibits the oncogenic properties of Met, the HGF receptor.

12 K252a, an indrocarbazole derivative, causes the membrane of myoblasts to enter a fusion-capable state

13 Efficient syntheses of novel C2'-alkylated (+/-)-K252a analogues

14 Promotion of skeletal muscle differentiation by K252a with tyrosine phosphorylation of focal adhesion: a possible involvement of small GTPase Rho.

15 K252a induces cell cycle arrest and apoptosis by inhibiting Cdc2 and Cdc25c.

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