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PK115-584

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This article, PK115-584, was written by RelentlessRecusant. Please do not edit this fiction without the writer's permission.

PK115-584
("Calphostin C")
Chemical information
IUPAC Nomenclature

1-[3,10-dihydroxy-12-[2-(4-hydroxyphenoxy)carbonyloxypropyl]-2,6,7, 11-tetramethoxy-4,9-dioxoperylen-1-yl]propan-2-yl benzoate

Chemical Formula

C44H38O14

Molecular Weight

790.76 g/mol

Solubility

DMSO or DMF

Clinical information
Clinical Usage
  • Colorectal cancer treatment
  • Central nervous cancer treatment
Mechanism of Action
  • PKC inhibitor (IC50 = 400 nM)
  • Wnt/β-catenin inhibitor (IC50 = 50 nM)
  • MLCK inhibitor (IC50 > 5 μM)
Route of Administration

Intravenous (IV)

Pharmacokinetic information
Bioavailability

Low

Metabolism

Hepatic metabolism

Elimination Half-Life

Low

  [Source]

PK115-584 (Calphostin C, UCN-1028C), IUPAC name 1-[3,10-dihydroxy-12-[2-(4-hydroxyphenoxy)carbonyloxypropyl]-2,6,7, 11-tetramethoxy-4,9-dioxoperylen-1-yl]propan-2-yl benzoate, is a small-molecule chemical inhibitor of Tcf4/β-catenin interaction, acting as a highly potent of canonical Wnt signaling in mammalian cells[1] However, it retains some promiscuity in biological targets, and also acts as an effective inhibitor of protein kinase C (PKC) and myosin light chain kinase (MLCK)[2]. It has an IC50 = 3.2 μM for inhibiting in vitro Tcf4/β-catenin interaction and an IC50 = 0.4 μM for inhibiting cell-based β-catenin-dependent luciferase transcription. It was originally isolated from a fungal source, designating PK115-584 as a pharmacognosy-derived natural product.

It was originally characterized as a Wnt signaling inhibitor by Lepourcelet et. al in 2004 in the United States of America as a part of a collaborative effort by members of the Dana-Farber Cancer Institute (DFCI), Brigham & Women's Hospital (BWH), Harvard Medical School (HMS), and the Novartis Institutes for BioMedical Research in Boston and Cambridge, Massachusetts and the University of California, Santa Cruz at Santa Cruz, California.

As of 2590, it is currently being marketed by Acumen Science Laboratories as a potent anticancer drug for colorectal cancer, and the compound's potent PKC and Wnt inhibitory activities are believed to synergistically converge on the inhibition of colorectal cancer proliferation and lend to the drug's potent activities. PK115-584 remains as a rationally-designed and highly-specific antitumor agent by inhibiting Wnt/β-catenin signaling, which has been extensively implicated in colorectal cancer[1]. Colorectal cancer in the 21st century accounted for the deaths of 55,000 Americans every year[1]. It is also a highly potent anticancer agent for the treatment of brain cancer, as Wnt signaling has been previously shown to be a potent modulator of adult neural stem cell (NSC) self-renewal.[3]

[edit] References

  1. ↑ 1.0 1.1 1.2 Lepourcelet et. al (2004). Small-molecule antagonists of the oncogenic Tcf/β-catenin protein complex. Cancer Cell (5): 91-102.
  2. ↑ BioMol. Specificities of Selected SER/THR Kinase Inhibitors.
  3. ↑ Kalani et. al (2008). Wnt-mediated self-renewal of neural stem/progenitor cells. Proceedings of the National Academy of Sciences (105): 16970–16975.



Anticancer Drugs (Acumen Science Laboratories): Chemical Biology and Oncology
A-83-01 (Colon Cancer) · Bicuculline (Brain Cancer) · BMS-354825 (Chronic Myeloid Leukemia) · Dorsomorphin/LDN-193189 (Lung Cancer) · Cyclopamine/Robotnikinin/SANT1 (Skin, Brain, Prostate, and Colon Cancers) · LY165163 (Brain Cancer) · PK115-584 (Colon and Brain Cancer)
Source · Edit


Chemical Biology: Small-Molecule Control of Biological Systems (RelentlessRecusant)
Biological Targets
Compound Names
Receptor Tyrosine Kinases A-83-01 (TGFβ/Activin) · BPIQ-II (EGFR) · Dorsomorphin/LDN-193189 (TGFβ/BMP) · SU5402 (FGFR)
Signaling Kinases A-769662 (AMPK) · BMS-354825 (BCR-ABL, Src)· BIO-Acetoxime (GSK3) · CHIR99021 (GSK3) · GO 6976 (PKC) · IMD-0354 (IκBa) · PD184352 (MAPK) · SB203580 (MAPK) · Y-27632 (ROCK)
G Protein-Coupled Receptor (+)-WIN-55212 (CB1/CB2) · ±-Sulpride (D2) · A 841720 (mGluR1) · BP-554 (5-HT1A) · Hh-Ag1.5 (Smo) · Cyclopamine/KAAD-Cyclopamine (Smo) · SANT1 (Smo) · SB-277011 (D3)
Ion Channels BAY K8644 (Cav1.2) · Bicuculline (GABAAR) · Cymarin (Na+/H+) · G-strophanthin (Na+/H+) · L-AP4 (Na+/H+) · Oxcarbazepine (Na+) · Resiniferatoxin (TRPV1) · Sarmentogenin (Na+/H+) · Theanine (AMPAR, NMDAR)
Transporters O-1783 (DAT) · WF-23 (DAT, SERT)
Nuclear Receptor All-trans retinoic acid (RAR/RXR) · GW501516 (PPARδ) · RU-486 (Nr3c1, Nr3c3)
Protein Phosphatases Endothall (PP2A)
Polypharmacological Phosphoserine (mGluR4) · PK115-584 (Tcf4/β-catenin, PKC) · Pluripotin · Reversine
Other 2C-E (DAT) · 4-methoxyphenyl-HTI-286 (α/β-tubulin) · Compound E/DAPT (presenilin-1) · D-cysteine · D-phenylalanine · Flurbiprofen (COX) · JZL184 (MAGL) · QS11 (RAFGAP1) · RO-28-1675 (glucokinase) · Robotnikinin (Shh) · Selegiline (MAOB)
Uncharacterized Neuropathiazol
Libraries Kinase Inhibitor Library
Publications
Small molecule-mediated manipulation of the adult human induces selective and reversible control of physiological and psychological phenotype (Rubin et. al, 2590. Nature Medicine)
Source · Edit
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