1373615-35-0 Usage
Description
PF-5274857 is a potent and selective Smoothened (Smo) antagonist that inhibits the Hedgehog (Hh) signaling pathway. It is a pharmaceutical compound with the ability to penetrate the blood-brain barrier, making it a promising candidate for various applications in the medical field.
Uses
Used in Pharmaceutical Industry:
PF-5274857 is used as a therapeutic agent for targeting the Hedgehog signaling pathway, which plays a crucial role in various diseases, including cancer and neurological disorders. By inhibiting this pathway, PF-5274857 can potentially slow down or halt the progression of these diseases.
Used in Cancer Treatment:
PF-5274857 is used as an anticancer agent, particularly in the treatment of cancers where the Hedgehog signaling pathway is overactive or aberrantly regulated. It can help in reducing tumor growth and progression by blocking the abnormal signaling that contributes to cancer development.
Used in Neurological Disorders:
PF-5274857 is used as a potential treatment for neurological disorders associated with the dysregulation of the Hedgehog signaling pathway, such as Alzheimer's disease and other neurodegenerative conditions. Its ability to penetrate the blood-brain barrier allows it to directly target the affected areas in the brain.
Used in Drug Delivery Systems:
To enhance the efficacy and bioavailability of PF-5274857, various drug delivery systems can be employed. These systems can help improve the compound's delivery to the target site, reduce side effects, and increase its overall therapeutic potential.
Biological Activity
pf-5274857 is an inhibitor of hedgehog (hh) signaling pathway and is identified as a potent and selective antagonist of smoothened (smo) with an ic50 of 5.8 nm.smoothened, a g protein-coupled receptor, is a component of the hedgehog signaling pathway and is conserved from flies to humans. this protein is the molecular target of the teratogen cyclopamine. smo can act as an oncogene and the activation of smo mutations leads to unregulated activation of the hedgehog pathway and cancer.in mef cells, treatment of pf-5274857 completely blocked shh-induced hh pathway activity, which was measured by the transcriptional activity of smo downstream gene gli1.
Enzyme inhibitor
This brain-penetrating Smoothened (Smo) antagonist (FW = 436.96 g/mol; CAS 1373615-35-0), also known as 1-(4-(5-chloro-4-(3,5-dimethylpyridin- 2-yl)pyridin-2-yl)piperazin-1-yl)-3-(methylsulfonyl)propan-1-one, potentlyand selectively inhibits Hedgehog (Hh) signaling (IC50 = 5.8 nM; Ki = 4.6 nM). PF-5274857 elicits robust antitumor activity in a mouse model of medulloblastoma (IC50 = 8.9 nmol/L), with down-regulation of Gli1, a marker closely linked to the tumor growth inhibition in patched (+/-) medulloblastoma mice. PF-5274857 also inhibits Smo activity within the brain of primary medulloblastoma mice, improving survival. PF-5274857 is orally available and metabolically stable in vivo. Other Hedgehog inhibitors include: GANT61, BMS-833923, Purmorphamine, SANT-1, LY2940680, Cyclopamine, LDE225 (or NVP-LDE225, Erismodegib), Vismodegib (GDC-0449)
in vivo
pf-5274857 showed anti-tumor activity in a mouse medulloblastoma model with ic50 of 8.9 nm. pf-5274857 also shows significant dose-dependent tumor growth inhibition (tgi) and induces tumor regression. in skin tissue, downregulation of gli1 and gli2 is also observed with a similar time course by pf-52748571.
references
1. rohner a, spilker me, lam jl, et al. effective targeting of hedgehog signaling in a medulloblastoma model with pf-5274857, a potent and selective smoothened antagonist that penetrates the blood-brain barrier. molecular cancer therapeutics.2012;11(1):57-65.
Check Digit Verification of cas no
The CAS Registry Mumber 1373615-35-0 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,3,7,3,6,1 and 5 respectively; the second part has 2 digits, 3 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 1373615-35:
(9*1)+(8*3)+(7*7)+(6*3)+(5*6)+(4*1)+(3*5)+(2*3)+(1*5)=160
160 % 10 = 0
So 1373615-35-0 is a valid CAS Registry Number.
1373615-35-0Relevant articles and documents
PYRIDINE- 2- DERIVATIVES AS SMOOTHENED RECEPTOR MODULATORS
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, (2012/05/05)
The present application relates to compounds of Formula (I), and Formula (II), or pharmaceutically acceptable salt thereof, wherein A, X, Y, Z, e, f, R1, R2, R3, R4, R5, R5b, R6, R7, R8, R9, R10, R11,R20, R21, R22 and R23 are defined herein. These novel pyridine derivatives that are useful in therapy, in particular for treating diseases or conditions mediated by Smo, including the treatment of abnormal cell growth, such as cancer, in mammals. Additional embodiments relate to methods of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
