Abstract
GSK3B has been an interesting drug target in the pharmaceutical industry. Its dysfunctional expression has prognostic significance in the top 3 cause of death associated with non-communicable diseases (cancer, Alzheimer's disease and type 2 diabetes). Previous studies have shown clearly that inhibiting GSK3B has proven therapeutic significance in Alzheimer's disease, but its contribution to various cancers has not been clearly resolved. In this study we report the contribution and prognostic significance of GSK3B to two breast cancer subtypes; ductal carcinoma in-situ (DCIS) and invasive ductal carcinoma (IDC) using the Oncomine platform. We performed high throughput screening using molecular docking. We identified BT-000775, a compound that was subjected to further computational hit optimization protocols. Through computational predictions, BT-000775 is a highly selective GSK3B inhibitor, with superior binding affinity and robust ADME profiles suitable for the patho-physiological presentations.
Highlights
Alzheimer disease (AD) is a neurodegenerative disorder which happens to be the most common cause of age-related dementia currently accounting for up to 70% of all dementia cases based on clinical diagnostic criteria [1]
The World Alzheimer Report 2010 evaluated that ageing of the global population will aggravate economic effect of dementia more than that of cancer, heart disease, and stroke combined [3,4] and that by 2050, an estimated 14–16 million people in the U.S alone will be diagnosed with the disease if novel treatments to prevent or delay the onset of AD are not identified [5]
GSK3B is a valid drug target for AD, ductal carcinoma in-situ (DCIS) and invasive ductal carcinoma (IDC) Breast Cancer A total of 14 datasets, which compared the expression of GSK3B in normal tissues with Breast cancer (BC) tissues, were retrieved from the Oncomine platform
Summary
Alzheimer disease (AD) is a neurodegenerative disorder which happens to be the most common cause of age-related dementia currently accounting for up to 70% of all dementia cases based on clinical diagnostic criteria [1]. The World Alzheimer Report 2010 evaluated that ageing of the global population will aggravate economic effect of dementia more than that of cancer, heart disease, and stroke combined [3,4] and that by 2050, an estimated 14–16 million people in the U.S alone will be diagnosed with the disease if novel treatments to prevent or delay the onset of AD are not identified [5]. (NFTs)–formed mainly by GSK3B mediated hyper phosphorylation of tau proteins [7]. In experimental models of AD, GSK3β has been shown to cause hyper phosphorylation of Tau, leading to microtubule disassembly and loss of neuronal function [8]. The dysregulation of GSK3β activity has crucial effects in key pathological features of AD and its atypical activation may be involved in the initial and primary event in the physiopathology of AD [10]
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