Products

LDN-57444 is a specific inhibitor (Ki = 0.4 ?M) against Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a

member of deubiquitinating enzymes (DUBs). LDN-57444 increased proliferation of SH-SY5Y cells, a UCH-

L1-expressing neuroblastoma line. [1]

 

As expression of UCH-L1 is highly specific to neurons and to cells of the diffuse neuroendocrine system and

their tumors, LDN-57444 is a useful tool for studying the roles of UCH-L1 in Alzheimer’s disease,

Parkinson’s disease, and other neurological disorders. [2,3]

References

1. Liu Y, et al. Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell

   line. Chem Biol. 2003; 10(9):837-46. Pubmed ID: 14522054

2. Cartier AE, et al. Regulation of synaptic structure by ubiquitin C-terminal hydrolase L1. J Neurosci. 2009; 29

   (24):7857-68. Pubmed ID: 19535597

3. Zhang M, et al. Control of BACE1 degradation and APP processing by ubiquitin carboxyl-terminal

   hydrolase L1. J Neurochem. 2012; 120(6):1129-38. Pubmed ID: 22212137

VX-770 (Ivacaftor) is a CFTR potentiator and has been shown to potentiate normal CFTR, as well as CFTR

with G551D and F508-del mutations. Ivacaftor directly binds to the ion channel, causes conformation change

and open the ion channel to improve chloride transportation. In primary cultured human CF bronchial epithelia

(HBE) carrying the G551D and F508del CFTR mutations, Ivacaftor (10 ?M) potently increases the forskolin-

stimulated Cl- secretion with an EC50 of 236 nM. [1]

 

VX-770 (Ivacaftor) is approved for cystic fibrosis patients with G551D mutation, and has shown efficacy in a

patient with S549N mutation. [2]

1. Van Goor F et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. , Proc

   Natl Acad Sci U S A. 2009; 106(44):18825-30. Pubmed ID: 19846789

2. McGarry ME and Nielson DW. Normalization of sweat chloride concentration and clinical improvement with

   ivacaftor in a patient with cystic fibrosis with mutation S549N. Chest. 2013; 144(4):1376-8.

   Pubmed ID: 24081349

BAY-73-4506 (Regorafenib) is an orally active and highly potent inhibitor against multiple tyrosine kinases,

including VEGFR1/2/3, PDGFR?, Kit, RET and Raf-1. Regorafenib inhibits the proliferation of HUVEC cells

stimulated with VEGF, and inhibits FGFR signaling in breast cancer MCF-7 cells stimulated with FGF.

Regorafenib is anti-angiogenic due to its inhibitions against VEGFR2-TIE2 tyrosine kinase. [1]

Co-administration of Regorafenib and a PI3K/Akt inhibitor (MK-2206) clearly demonstrated synergistic effect

in a HCT116 xenocraft mouse model [2]. Regorafenib is currently being studied as a potential treatment

option in multiple tumor types, and has recently be approved in treating patients with Metastatic Colorectal

cancer. [3]

References

1. Wilhelm SM et al, Regorafenib (BAY 73-4506): a new oral multi-kinase inhibitor of angiogenic, stromal and

   oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011; 129:245-55

   Pubmed ID: 21170960

2. Sajithlal GB et al. Sorafenib/regorafenib and phosphatidyl inositol 3 kinase/thymoma viral proto-oncogene

   Inhibition interact to kill tumor cells. Mol Pharmacol. 2013; 84(4):562-71. Pubmed ID: 23877009

3. Carter NJ. Regorafenib: a review of its use in previously treated patients with progressive metastatic

   colorectal cancer. Drugs Aging. 2014; 31(1):67-78. Pubmed ID: 24276917

Zearalenone is a heat-resistant mycotoxin produced by fungi in food and animal feeds [1]. It acts as an

estrogen receptor agonist and can cause hormonal effects in animal species such as the pig [2]. Evidence

for Zearalenone effects have been observed in a wide variety of animals. The association between

Zearalenone exposure and human diseases remains speculative at present; it has been considered as a

possible causative agent in outbreaks of precocious pubertal changes in young children and has been

suggested to have a possible involvement in human cervical cancer. [3,4]

References:

LGK974 is a potent and orally active Wnt pathway inhibitor with an IC50<1 nM in the Wnt signaling assay [1].

It inhibits acylation of Wnt proteins by Porcupine (Porcn). LGK974 specifically blocks the proliferation of

pancreatic cancer cells that have up-regulated Wnt signaling caused by carrying inactive mutations in a

Ubiquitin E3 ligase, RNF43 [2].

 

LGK974 robustly suppressed Wnt signaling in vivo resulting in tumor regression in a murine breast cancer

model driven by MMTV-Wnt1, and showed excellent efficacy in xenograft models of head and neck

squamous cell carcinoma and pancreatic cancer [3]. Currently LGK974 is in the Phase I study to treat

patients with different types of Wnt signaling-driven cancers [4].

References:

1. Shifeng Pan. Discovery of LGK974: A selective Porcupine inhibitor targeting Wnt signaling in cancer. AACR

   Annual Meeting 2013.

2. Jiang X, et al. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal

   adenocarcinoma. Proc Natl Acad Sci USA. 2013; 110(31):12649-54. Pubmed ID: 23847203

3. Liu J, et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci

   U S A. 2013; 110(50):20224-9 Pubmed ID: 24277854

4. http://clinicaltrials.gov/show/NCT01351103