A5107336789- Prostate Cancer Treatment and Research
- Estrogen and related hormone effects
- Radiopharmaceutical Chemistry and Applications
- Hormonal and reproductive studies
- Ubiquitin and proteasome pathways
- Computational Drug Discovery Methods
- Cancer, Lipids, and Metabolism
- Protein Degradation and Inhibitors
- Molecular Biology Techniques and Applications
- 14-3-3 protein interactions
- Mass Spectrometry Techniques and Applications
- Genomics and Chromatin Dynamics
- Cancer Genomics and Diagnostics
- RNA Interference and Gene Delivery
- Pharmacogenetics and Drug Metabolism
- Cytokine Signaling Pathways and Interactions
- Peptidase Inhibition and Analysis
- HER2/EGFR in Cancer Research
- Microbial Natural Products and Biosynthesis
- Cancer therapeutics and mechanisms
- Cancer-related gene regulation
- Lung Cancer Research Studies
- Polyamine Metabolism and Applications
- Steroid Chemistry and Biochemistry
- Material Science and Thermodynamics
University of British Columbia
2011-2023
The Prostate Centre
2021
Protéomique, Réponse Inflammatoire et Spectrométrie de Masse
2019-2021
Université de Lille
2020-2021
Helwan University
2013
University of Münster
2013
The androgen receptor (AR) is a pivotal drug target for the treatment of prostate cancer, including its lethal castration-resistant (CRPC) form. All current non-steroidal AR antagonists, such as hydroxyflutamide, bicalutamide, and enzalutamide, binding site receptor, competing with endogenous androgenic steroids. Several mutations in this have been associated poor prognosis resistance to conventional cancer drugs. In order develop an effective CRPC therapy, it crucial understand effects...
The androgen receptor (AR) is the best studied drug target for treatment of prostate cancer. While there are a number drugs that AR, they all work through same mechanism action and prone to development resistance. There large unmet need novel AR inhibitors which alternative mechanism(s). Recent studies have identified site on called binding function 3 (BF3) involved into transcriptional activity. In order identify BF3 site, we conducted large-scale in silico screen followed by experimental...
The majority of computational methods for predicting toxicity chemicals are typically based on "nonmechanistic" cheminformatics solutions, relying an arsenal QSAR descriptors, often vaguely associated with chemical structures, and employing "black-box" mathematical algorithms. Nonetheless, such machine learning models, while having lower generalization capacity interpretability, achieve a very high accuracy in various endpoints, as unambiguously reflected by the results recent Tox21...
The human androgen receptor (AR) is considered as a master regulator in the development and progression of prostate cancer (PCa). As resistance to clinically used anti-AR drugs remains major challenge for treatment advanced PCa, there pressing need new therapeutic avenues. In this study, we identified binding site on DNA domain (DBD) utilized virtual screening discover set micromolar hits target. Through further exploration most potent hit (1), structural analogue (6) was demonstrating...
Small-molecule drug design is a complex and iterative decision-making process relying on pre-existing knowledge driven by experimental data. Low-molecular-weight chemicals represent an attractive therapeutic option, as they are readily accessible to organic synthesis can easily be characterized.1 Their potency well pharmacokinetic pharmacodynamic properties systematically rationally investigated ultimately optimized via expert science behind medicinal chemistry methods of computer-aided...
Recent explosive growth of 'make-on-demand' chemical libraries brought unprecedented opportunities but also significant challenges to the field computer-aided drug discovery. To address this expansion accessible universe, molecular docking needs accurately rank billions structures, calling for development automated hit-selecting protocols minimize human intervention and error. Herein, we report an artificial intelligence-driven virtual screening pipeline that utilizes Deep Docking with...
The androgen receptor (AR) is one of the most studied drug targets for treatment prostate cancer. However, all current anti-androgens directly interact with AR at binding site, which prone to resistant mutations, calling new strategies inhibition. study represents first attempt use virtual screening identify inhibitors activation function-2 (AF2) human AR. By combining large-scale docking experimental approaches, we were able several small molecules that AF2 and effectively prevent...
The human androgen receptor (AR) is a proven therapeutic target in prostate cancer. All current antiandrogens, such as Bicalutamide, Flutamide, Nilutamide, and Enzalutamide, the buried hydrophobic binding pocket of this protein. However, effective resistance mechanisms against these therapeutics exist mutations occurring at site. To overcome limitations, surface AR called function 3 (BF3) was characterized an alternative for small molecule therapeutics. A number inhibitors directly targeting...
To overcome resistance to conventional anti-androgens of human androgen receptor (AR), the allosteric site AR binding function 3 (BF3) was investigated as an alternative target for small molecule therapeutics. A library 1H-indole-2-carboxamides were discovered BF3 inhibitors and exhibited strong antiproliferative activity against LNCaP enzalutamide-resistant prostate cancer cell lines. Several lead compounds may prove particular benefit a novel treatment castration-resistant cancers.
The heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a versatile RNA-binding protein playing critical role in alternative pre-mRNA splicing regulation cancer. Emerging data have implicated hnRNP as central player regulatory circuit involving its direct transcriptional control by c-Myc oncoprotein and the production of constitutively active ligand-independent splice variant androgen receptor, AR-V7, which promotes castration-resistant prostate cancer (CRPC). As there an urgent need...
Prostate cancer patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer. Resistance can occur when mutations in the receptor (AR) render anti-androgen drugs ineffective or through expression of constitutively active splice variants lacking binding domain entirely (e.g., ARV7). In this study, we are reporting discovery a novel AR-NTD covalent inhibitor 1-chloro-3-[(5-([(2S)-3-chloro-2-hydroxypropyl]amino)naphthalen-1-yl)amino]propan-2-ol...
Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer (PCa). The AR hormone-binding site (HBS) is intensively studied represents target area for current antiandrogens including Bicalutamide structurally related Enzalutamide. As resistance to invariably emerges advanced cancer, there exists high medical need identification novel antagonists different chemotypes. Given wealth structural information on complex with variety ligands, we have applied an...
Human androgen receptor (AR) is a hormone-activated transcription factor that an important drug target in the treatment of prostate cancer. Current small-molecule AR antagonists, such as enzalutamide, compete with androgens bind to steroid-binding pocket ligand-binding domain (LBD). In castration-resistant cancer (CRPC), resistance can manifest through AR-LBD mutations convert antagonists into agonists, or by expression variants lacking LBD. Such underscores importance novel ways targeting...
The inhibition of the androgen receptor (AR) is an established strategy in prostate cancer (PCa) treatment until drug resistance develops either through mutations ligand-binding domain (LBD) portion or its deletion. We previously identified a druggable pocket on DNA binding (DBD) dimerization surface AR and reported several potent inhibitors that effectively disrupted DBD-DBD interactions consequently demonstrated certain antineoplastic activity. Here we describe further development small...
Abstract The development of new antiandrogens, such as enzalutamide, or androgen synthesis inhibitors like abiraterone has improved patient outcomes in the treatment advanced prostate cancer. However, due to drug resistance and tumor cell survival, a majority these patients progress refractory state castration-resistant cancer (CRPC). Thus, newer therapeutic agents better understanding their mode action are needed for treating CRPC patients. We demonstrated previously that targeting Binding...
Resistance to drug treatments is common in prostate cancer (PCa), and the gain-of-function mutations human androgen receptor (AR) represent one of most dominant drivers progression resistance AR pathway inhibitors (ARPI). Previously, we evaluated vitro response 24 mutations, identified men with castration-resistant PCa, five antagonists. In current work, 44 additional PCa-associated mutants, reported literature, thus expanded study effect darolutamide a total 68 mutants. Unlike other...
The human androgen receptor plays a major role in the development and progression of prostate cancer represents well-established drug target. All clinically approved antagonists possess similar chemical structures exhibit same mode action on receptor. Although initially effective, resistance to these usually develops quickly progresses castration-resistant metastatic states. Yet even late-stage patients, is critical for disease. Thus, there continuing need novel classes that could help...
Abstract Introduction Current approaches to inhibit oestrogen receptor-alpha (ERα) are focused on targeting its hormone-binding pocket and have limitations. Thus, we propose that inhibitors bind a coactivator-binding ERα, called activation function 2 (AF2), might overcome some of these Methods In silico virtual screening was used identify small-molecule ERα AF2 inhibitors. These compounds were screened for inhibition transcriptional activity using stably transfected T47D-KBluc cell line. A...
Resistance to androgen-receptor (AR) directed therapies is, among other factors, associated with Myc transcription factors that are involved in development and progression of many cancers. Overexpression N-Myc protein prostate cancer (PCa) leads its transformation advanced neuroendocrine (NEPC) currently has no approved treatments. a short half-life but acts as an NEPC stimulator when it is stabilized by forming protective complex Aurora A kinase (AURKA). Therefore, dual-inhibition AURKA...