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The Hedgehog (Hh) pathway plays a critical role during embryonic development by controlling cell patterning, growth and migration. In adults, the function of Hh pathway is curtailed to tissue repair and maintenance. Aberrant reactivation of Hh signaling has been linked to tumorigenesis in various cancers, such as basal cell carcinoma (BCC) and medulloblastoma. The Smoothened (Smo) receptor, a key component of the Hh pathway which is central to the signaling transduction, has emerged as an attractive therapeutic target for the treatment of human cancers. Taking advantage of the availability of several crystal structures of Smo in complex with different antagonists, we have previously conducted a molecular docking-based virtual screening to identify several compounds which exhibited significant inhibitory activity against the Hh pathway activation (IC < 10 μM) in a Gli-responsive element (GRE) reporter gene assay. The most potent compound (ChemDiv ID C794-1677: 47 nM) showed comparable Hh signaling inhibition to the marketed drug vismodegib (46 nM). Herein, we report our structural optimization based on the virtual screening hit C794-1677. Our efforts are aimed to improve potency, decrease cLogP, and remove potentially metabolic labile/toxic pyrrole and aniline functionalities presented in C794-1677. The optimization led to the identification of numerous potent compounds exemplified by 25 (7.1 nM), which was 7 folds more potent compared with vismodegib. In addition, 25 was much less lipophilic compared with C794-1677 and devoid of the potentially metabolic labile/toxic pyrrole and aniline functional groups. Furthermore, 25 exhibited promising efficacy in inhibiting Gli1 mRNA expression in NIH3T3 cells with either wildtype Smo or D473H Smo mutant. These results represented significant improvement over the virtual screening hit C794-1677 and suggested that compound 25 can be used as a good starting point to support lead optimization.
This article was published in the following journal.
Name: European journal of medicinal chemistry
Using the available structural information of the chemokine receptor CXCR4, we present hit finding and hit exploration studies that make use of virtual fragment screening, design, synthesis and struct...
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Retinoid X receptor alpha (RXRα), a central member of the nuclear receptor superfamily and a key regulator of many signal transduction pathways, has been an attractive drug target. We previously disc...
Primary cilia are required for Smoothened to transduce vertebrate Hedgehog signals, but how Smoothened accumulates in cilia and is activated is incompletely understood. Here, we identify cilia-associa...
The integration of pharmacophore-based 3D QSAR modeling and virtual screening in safety profiling: A case study to identify antagonistic activities against adenosine receptor, A2A, using 1,897 known drugs.
Safety pharmacology screening against a wide range of unintended vital targets using in vitro assays is crucial to understand off-target interactions with drug candidates. With the increasing demand f...
Using a virtual reality program in screening and treatment of ADHD.
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Colon cancer is the second leading cause of cancer death in North America. These deaths are preventable with proper screening. Fecal occult blood testing, virtual colonoscopy, and standard...
Investigating how neuropathic limb pain, including phantom limb pain or complex regional pain syndrome, is affected by virtual reality. While several studies have looked into virtual reali...
The objective of this study is to demonstrate that frequent atrio-ventricular (AV/PV) and inter-ventricular (V-V) delay optimization using QuickOpt in patients with CRT-D device results in...
Treatment technique in a virtual environment which allows the participant to experience a sense of presence in an immersive, computer-generated, three-dimensional, interactive environment that minimizes avoidance behavior and facilitates emotional involvement. (from Curr Psychiatry Rep (2010) 12:298)
A patched receptor for several HEDGEHOG PROTEINS that associates with the SMOOTHENED RECEPTOR to modulate hedgehog signaling. It is also a TUMOR SUPPRESSOR PROTEIN; mutations in the patched-1 gene are associated with BASAL CELL NEVUS SYNDROME; SQUAMOUS CELL CARCNIOMA of the ESOPHAGUS; trichoepitheliomas, and CARCINOMA, TRANSITIONAL CELL of the URINARY BLADDER.
The identification of selected parameters in newborn infants by various tests, examinations, or other procedures. Screening may be performed by clinical or laboratory measures. A screening test is designed to sort out healthy neonates (INFANT, NEWBORN) from those not well, but the screening test is not intended as a diagnostic device, rather instead as epidemiologic.
A frizzled-like, G-protein-coupled receptor that associates with PATCHED RECEPTORS to transduce signals from HEDGEHOG PROTEINS and initiate hedgehog signaling to ZINC FINGER PROTEIN GLI1. It may normally inhibit signaling in the absence of SONIC HEDGEHOG PROTEIN binding to PATCHED RECEPTOR-1.
Testing or screening required by federal, state, or local law or other agencies for the diagnosis of specified conditions. It is usually limited to specific populations such as categories of health care providers, members of the military, and prisoners or to specific situations such as premarital examinations or donor screening.
There are three main types of skin cancer: basal cell carcinoma, squamous cell carcinoma and malignant melanoma. Basal cell carcinoma Basal cell carcinoma, or BCC, is a cancer of the basal cells at the bottom of the epidermis. It’s very common ...
Bioinformatics is the application of computer software and hardware to the management of biological data to create useful information. Computers are used to gather, store, analyze and integrate biological and genetic information which can then be applied...