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The Translational Applications of Using Oxadiazole-Derived Small-Molecule Agents to Induce Protein Degradation Pathways
Başlık:
The Translational Applications of Using Oxadiazole-Derived Small-Molecule Agents to Induce Protein Degradation Pathways
Yazar:
Fang, Chun-Sheng, author.
ISBN:
9780438099258
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (107 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-11(E), Section: B.
Advisors: Karl Werbovetz Committee members: James Fuchs; Jack Yalowich.
Özet:
Carcinogenesis is a consequence of genetic mutations that lead normal cells to become cancer cells. The unusual expression or mutation of oncogenic proteins such as EGFR, c-Met and YAP will promote cancer cell growth. Therefore, those oncogenic proteins are the potential targets to inhibit cancer growth. Targeting oncoprotein degradation using proteasomes or lysosomes to clear damaged proteins becomes a promising strategy in anti-cancer drug discovery, so we initiated a screen of oxadiazole-derived compound libraries to identify agents capable of facilitating the degradation of EGFR and c-Met by using the breast cancer cell model MDA-MB-231. In our libraries, compound 1 exhibits modest ability to concomitantly down-regulate the expression of EGFR and c-Met. In MDA-MB-231 cells, we conducted several optimization cycles based on the modifications of ring A, ring B, and linker C of compound 1, which generated four series of derivatives consisting of a total of fifty-one derivatives. Replacement of the amide linker with a urea, followed by substitutions on ring A with various functional groups at position 3 and/or 4 generated an array of derivatives (series IV, 25 -- 51) with a broad range of anti-proliferative activities, especially compound 48 which exhibited a suppressive effect on the expression of both EGFR and c-Met. Although compound 47 was structurally similar to compound 48 (acetyl- versus cyclopropyl-), compound 47 lacked appreciable activity in inhibiting the expression of EGFR or c-Met, which warrants further attention in terms of the underlying mechanism.
Notlar:
School code: 0168
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
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XX(696415.1) | 696415-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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