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LDN-193189

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This article, LDN-193189, was written by RelentlessRecusant. Please do not edit this fiction without the writer's permission.

LDN-193189
("DM-3189")
Chemical information
IUPAC Nomenclature

4-(6-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinoline

Chemical Formula

C25H22N6

Molecular Weight

406.48 g/mol

Solubility

DMSO

Clinical information
Clinical Usage
  • Non-small-cell lung carcinoma (NSCLC) lung cancer treatment[1][2]
  • Fibrodysplasia ossificans progressiva (FOP) treatment[3]
Mechanism of Action

ALK2, ALK3, and ALK6 (TGFβ/BMP) inhibitor (IC50 = 49 nM)[4]

Route of Administration
  • Oral
  • Intraperitoneal (IP)
Pharmacokinetic information
Metabolism

Hepatic metabolism[4]

Elimination Half-Life

Low (Plasma t1/2 = 1.6 hours)[4]

  [Source]

LDN-193189, otherwise known as DM-3189, IUPAC name 4-(6-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinoline, is a highly potent small-molecule chemical inhibitor of ALK2, ALK3, and ALK6, protein tyrosine kinases (PTK), inhibiting members of the ALK1 and ALK3 families of type I TGFβ receptors, inhibiting the transmission of multiple biological signals, including BMP2, BMP4, BMP6, BMP7, and Activin cytokine signals and inhibiting BMP signaling and subsequent SMAD phosphorylation.[4]

LDN-193189 shows significant in vivo clinical utility, and when administered to a constitutively-active Alk2 receptor mouse model, when administered 3 mg/kg intraperitoneally every twelve hours, inhibits fibrodysplasia ossificans progressiva (FOP) and ectopic ossification.[3] The role of BMP2 signals in the growth and angiogenesis of non-small-cell lung carcinoma (NSCLC) also suggest LDN-193189 may be a potent inhibitor of lung tumors.[1][2]

It was derived from structure-activity relationship (SAR) studies of Dorsomorphin, otherwise known as Compound C, IUPAC name 6-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine.[5] Dorsomorphin itself shows useful applications in stem cell biology and regenerative medicine, and directs in vitro differentiation of embryonic stem (ES) cells to a cardiomyocyte lineage at the expense of endothelial, smooth muscle, and hematopoietic alternate cell fates.[6]

[edit] References

  1. ↑ 1.0 1.1 Langenfeld et. al (2003). The mature bone morphogenetic protein-2 is aberrantly expressed in non-small cell lung carcinomas and stimulates tumor growth of A549 cells. Carcinogenesis (24): 1445-1454.
  2. ↑ 2.0 2.1 Langenfeld and Langenfeld (2004). Bone Morphogenetic Protein-2 Stimulates Angiogenesis in Developing Tumors. Molecular Cancer Research (2), 141–149.
  3. ↑ 3.0 3.1 Yu et. al (2008). BMP type I receptor inhibition reduces heterotopic ossification. Nature Medicine (14): 1363-1369.
  4. ↑ 4.0 4.1 4.2 4.3 Cuny et. al (2008). Structure–activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors. Bioorganic & Medicinal Chemistry Letters (18): 4388–4392.
  5. ↑ Yu et. al (2008). Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nature Chemical Biology (4): 33-41.
  6. ↑ Hao et. al (2008). Dorsomorphin, a Selective Small Molecule Inhibitor of BMP Signaling, Promotes Cardiomyogenesis in Embryonic Stem Cells. PLoS One (3): e2904.



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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