From epoxomicin to carfilzomib: chemistry, biology, and medical outcomes.
From epoxomicin to carfilzomib: chemistry, biology, and medical outcomes.
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DOI：
10.1039/c3np20126k
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发表时间：
2013-05
影响因子：
11.9
通讯作者：
Crews CM
中科院分区：
文献类型：
--
作者：
Kim KB;Crews CM
由于其最终临床应用的前景不佳，发现具有生物活性的天然产品后的最初热情往往转瞬即逝。尽管如此，现代生物学的不断变化的景观有一个不断的需要分子探针，可以帮助我们了解生物过程。在Bristol-Myers Squibb最初发现环氧霉素是一种微生物抗肿瘤天然产物后，由于其肽结构和潜在的不稳定环氧酮药效团，环氧霉素被认为不适合开发。尽管有其缺点，环氧霉素的药效团被发现提供前所未有的选择性的蛋白酶体。环氧霉素还用作产生具有改善活性的合成四肽环氧酮YU-101的支架，YU-101成为卡非佐米（Kyprolis ™）的母体先导化合物，卡非佐米是最近批准的多发性骨髓瘤治疗剂。在这个合理药物设计和高通量筛选的时代，将活性天然产物转化为批准的治疗方法的前景往往很渺茫。然而，通过了解从发现环氧霉素开始到在临床上成功使用卡非佐米结束的旅程，我们可能会发现新的见解，了解基于天然产物的药物发现成功的关键。
The initial enthusiasm following the discovery of a pharmacologically active natural product is often fleeting due to the poor prospects for its ultimate clinical application. Despite this, the ever-changing landscape of modern biology has a constant need for molecular probes that can aid in our understanding of biological processes. After its initial discovery by Bristol-Myers Squibb as a microbial anti-tumor natural product, epoxomicin was deemed unfit for development due to its peptide structure and potentially labile epoxyketone pharmacophore. Despite its drawbacks, epoxomicin’s pharmacophore was found to provide unprecedented selectivity for the proteasome. Epoxomicin also served as a scaffold for the generation of a synthetic tetrapeptide epoxyketone with improved activity, YU-101, which became the parent lead compound of carfilzomib (Kyprolis™), the recently approved therapeutic agent for multiple myeloma. In this era of rational drug design and high-throughput screening, the prospects for turning an active natural product into an approved therapy are often slim. However, by understanding the journey that began with the discovery of epoxomicin and ended with the successful use of carfilzomib in the clinic, we may find new insights into the keys for success in natural product-based drug discovery.
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影响因子：
2.7
作者：
Jagannath, Sundar;Vij, Ravi;Siegel, David S.
通讯作者：
Siegel, David S.
影响因子：
20.3
作者：
Siegel, David S.;Martin, Thomas;Jagannath, Sundar
通讯作者：
Jagannath, Sundar
影响因子：
3.5
作者：
Schreiber, SL
通讯作者：
Schreiber, SL
影响因子：
3.3
作者：
HANADA, M;SUGAWARA, K;OKI, T
通讯作者：
OKI, T
DOI：
10.1111/j.1749-6632.2001.tb11356.x
发表时间：
2001-01-01
期刊：
NEW VISTAS IN THERAPEUTICS, FROM DRUG DESIGN TO GENE THERAPY: DRUG-RESISTANT TUBERCULOSIS, FROM MOLECULES TO MACRO-ECONOMICS
影响因子：
--
作者：
Cragg, GM;Newman, DJ
通讯作者：
Newman, DJ