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The Use of Small Particle Catalysts in Pursuit of Green and Sustainable Chemistry
Published in Ahindra Nag, Greener Synthesis of Organic Compounds, Drugs and Natural Products, 2022
The clinical development candidate was positioned in Phase I/Ib trials designed to treat ERα positive breast cancer as a selective estrogen receptor-degrader (SERD) with potential antineoplastic activity. The multi-step synthesis yield was optimized to produce very satisfactory step yields. A kilogram scale protocol was developed for a Suzuki−Miyaura cross-coupling step leading to the synthesis of LSZ 102. Early synthetic activities using an aqueous/organic solvent medium were complicated by the formation of by-products including debrominated starting material requiring additional reaction workup. Reduction of the by-products became a major focus for synthetic design. Changes to the reaction catalyst and reaction composition continued to yield complex product compositions. The selection of the surfactant TPGS-750-M in water as a medium led to the improvement of product quality and selectivity. The change of reaction medium minimized typical impurities generated during the cross-coupling reaction.
Advancing Precision Medicine: Tailoring Personalized Therapies
Published in Shaker A. Mousa, Raj Bawa, Gerald F. Audette, The Road from Nanomedicine to Precision Medicine, 2020
Kyle B. Matchett, Niamh Lynam-Lennon, R. William Watson, James A. L. Brown
Dr. Luca Magnani’s group (Imperial College London, London, UK) demonstrated the importance of combining metabolic and mutation profiling in recurrent breast cancer patients. Endocrine therapies represent the gold standard for the treatment of breast cancer as first line treatments following curative surgery. Importantly, these therapies target, directly or indirectly, estrogen receptor alpha (ERα). Aromatase inhibitors (AIs) block estrogen production in various sites of the body, while Tamoxifen directly antagonizes estrogen receptor (ER) activation. Their similar method of action suggested that any resistance mechanisms would likewise be similar. However, recent evidence in metastatic patients revealed AI resistant tumors were particularly enriched for ER mutations, which were demonstrated to confer resistance [23, 24]. Moreover, drug-specific resistance mechanisms were not limited to ER mutations, as cholesterol biosynthesis can directly fuel ER activation via alternative ligands. Examining a cohort of matched primary-metastatic relapses treated uniquely with either Tamoxifen or AIs they observed AI-treated patients had significant amplification of the aromatase gene CYP19A1 and this amplification event was rare in patients treated with Tamoxifen [25]. This highlighted the importance of profiling tumor recurrence, allowing the monitoring of acquired resistance mechanisms and tailoring of treatments.
Advancing Precision Medicine: Tailoring Personalized Therapies
Published in Shaker A. Mousa, Raj Bawa, Gerald F. Audette, The Road from Nanomedicine to Precision Medicine, 2019
Kyle B. Matchett, Niamh Lynam-Lennon, R. William Watson, James A. L. Brown
Dr. Luca Magnani’s group (Imperial College London, London, UK) demonstrated the importance of combining metabolic and mutation profiling in recurrent breast cancer patients. Endocrine therapies represent the gold standard for the treatment of breast cancer as first line treatments following curative surgery. Importantly, these therapies target, directly or indirectly, estrogen receptor alpha (ERα). Aromatase inhibitors (AIs) block estrogen production in various sites of the body, while Tamoxifen directly antagonizes estrogen receptor (ER) activation. Their similar method of action suggested that any resistance mechanisms would likewise be similar. However, recent evidence in metastatic patients revealed AI resistant tumors were particularly enriched for ER mutations, which were demonstrated to confer resistance [23, 24]. Moreover, drug-specific resistance mechanisms were not limited to ER mutations, as cholesterol biosynthesis can directly fuel ER activation via alternative ligands. Examining a cohort of matched primary-metastatic relapses treated uniquely with either Tamoxifen or AIs they observed AI-treated patients had significant amplification of the aromatase gene CYP19A1 and this amplification event was rare in patients treated with Tamoxifen [25]. This highlighted the importance of profiling tumor recurrence, allowing the monitoring of acquired resistance mechanisms and tailoring of treatments.
Molecular Docking , ADMET and Pharmacokinetic properties predictions of some di-aryl Pyridinamine derivatives as Estrogen Receptor (Er+) Kinase Inhibitors
Published in Egyptian Journal of Basic and Applied Sciences, 2022
Sagiru Hamza Abdullahi, Adamu Uzairu, Gideon Adamu Shallangwa, Sani Uba, Abdullahi Bello Umar
Cancer is one of the most problematic and crucial health maladies that affect the globe. The undisputed concern about cancer and mortality rate is significantly expanding [1]. Recently, the targeted treatment of cancers such as breast cancer has been authorized. These inhibitive remedies neutralize cancer cells’ expansion by altering the specific molecules responsible for tumor growth and advancements, and as such, they curtail the damaging impacts of other nonselective chemotherapies and withstand the resistance reproduced by the prevailing anticancer medications [2]. Cancer remediation comprises numerous procedures that include prevention of angiogenesis that has been established to be a desirable scenario for inhibiting the progression of the tumor [3]. Breast cancer is one of the extensively identified cancers and the dominating reason for women’s cancer death globally according to GLOBOCAN 2012 [1]. One of the substantial superfamilies of nuclear receptors called estrogen receptor-α (ERα) is responsible for at least 70% of breast malignancy cases, and these categories of victims are classified as ER-positive (ER+) [4]. The continual activation of ERα by estrogens influences the multiplication of tumor cells, and hence, the blocking up of ER signaling by competitively binding to ER with anti-estrogens or estrogen deprivation is an important therapeutic method [5].
Impact of occupational cadmium exposure on bone in sewage workers
Published in International Journal of Occupational and Environmental Health, 2018
Mona M Taha, Heba Mahdy-Abdallah, Eman M Shahy, Khadiga S Ibrahim, Safaa Elserougy
Accumulating evidence suggested that estrogen seems to play a major role in male bone metabolism [16]. Estrogen effect was mediated by estrogen receptor (estrogen receptor alpha [ER-α]), which represents a member of steroid hormone receptor family. It functions as an important part of the hormone–receptor complex that promotes specific target genes expression [17]. Genetic alterations in multiple genes can account for this genetic component and ER-α gene represents one of the various potential candidates. Kim et al. [17] recorded that ER-α gene polymorphism is associated with osteoporosis development in Korean vegetarian men. Polymorphism of the ER-α gene found on intron 1 may affect gene expression and/or interindividual susceptibility in the estrogen hormone through its regulatory action in mRNA transcription. Other possibility was due to that this polymorphism might be associated with unidentified polymorphisms that is responsible for the quality or function of the protein encoded by the ER-α gene [18].