Synthesis & antitumor activity of epothilones B and D and their analogs
4区 · 医学
作者: Cheng, Hao ; Huang, Gangliang
Epothilone is a newly developed antitumor drug; its antitumor principle is to stop the cell cycle by binding to tubulin in tumor cells, promoting tubulin polymerization, inhibiting depolymerization of microtubules, and ultimately inducing apoptosis. There are many analogs of epothilone, such as epothilone B, epothilone D, ixabepilone, sagopilone, 21-amino-epothilone B and KOS-1584. Herein, the synthesis and antitumor activity of epothilones B and D were summed up. The antitumor activity of epothilone analogs was also compared. Synthesis of epothilone and its analogs is more complex, and choosing the proper synthetic method is very important. Moreover, these compounds have obvious antitumor effect. The epothilone and its analogs will continue to play an important role in the future treatment of tumors.
2015-01-01·OncoTargets and therapy4区 · 医学
Epothilones in epithelial ovarian, fallopian tube, or primary peritoneal cancer: a systematic review.
Ovarian cancer is the most lethal gynecologic malignancy; consequently, there is a need for effective therapies. Epothilones are microtubule-stabilizing agents that inhibit cell growth. Currently, patupilone and its four synthetic derivatives ixabepilone, BMS-310705, sagopilone, 20-desmethyl-20-methylsulfanyl epothilone B and epothilone D, as well as its derivative KOS-1584, are under clinical evaluation. This is the first systematic review conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines that synthesizes all available data emerging from trials and evaluates the efficacy and safety of epothilones in epithelial ovarian, primary fallopian tube, and primary peritoneal cancer. Despite the fact that epothilones have proven active in taxane-resistant settings in preclinical models, it is not yet clear from Phase II/III studies reviewed here that their clinical activity is superior to that of taxanes. Nevertheless, responses to epothilones have been observed in platinum-refractory/resistant ovarian cancer patients. Moreover, despite the shared mechanism of action of epothilones, their clinical profile seems clearly different, with diarrhea being the most common dose-limiting toxicity encountered with patupilone, whereas neutropenia and sensory neuropathy are the most common toxic effects observed with the other epothilones. In any case, randomized trials comparing epothilones with standard treatments seem warranted to define further the role of these agents, whereas biomarker analysis might further optimize patient selection.
2013-09-01·Anti-Cancer Agents in Medicinal Chemistry4区 · 医学
From Bacteria to Antineoplastic: Epothilones A Successful History
4区 · 医学
作者: Kaiser, Samuel ; Muller, Joseane John ; Froehlich, Pedro Eduardo ; Cristina Baggio Gnoatto, Simone ; Bergold, Ana Maria
Malignancies are a major cause of morbidity and mortality worldwide. Cancer is a cell disease, characterized by a deviation of the control mechanisms of proliferation and differentiation of cells. Among the treatments available, chemotherapy is often the first choice. Epothilones are a new class of anticancer drugs that act by interacting with cellular microtubules interrupting the proliferation of cancer cells. Many synthetic and semi-synthetic analogues of epothilones have been prepared aiming improvement in effectiveness and tolerability, based on QSAR studies. These analogues have been effective for treatment of tumors resistant to first-line treatments. Six new epothilones are being subjected to clinical trials. Ixabepilone (Ixempra®) was approved by FDA in 2007, patupilone is in phase III clinical trial for ovarian and peritoneum cancer. Sagopilone, desoxiepothilone and KOS-1584 are in phase II clinical trials, for the treatment of recurrent glioblastoma and advanced metastatic breast cancer, metastasic breast cancer and metastatic pulmonary cancer, respectively. Desoxiepothilone reached only phase II trials and BMS-310705 reached phase III/IV trials, but were not approved for clinical use due to adverse effects such as neurotoxicity and severe diarrhea, which were dose-limiting. Furthermore, the low t1/2 (40h) in comparison with other class analogues, does not recommend the clinical use of this derivative. Some other synthetized epothilones presented antineoplastic activity in vitro, but are not yet submitted to clinical studies. Neuropathies and diarrhea are adverse effects presented by some substances of this class of anticancer drugs.
HAYWARD, Calif., July 26 /PRNewswire-FirstCall/ -- Kosan Biosciences Incorporated announced that Robert G. Johnson, Jr., M.D., Ph.D., Kosan's Chief Executive Officer, has been appointed to the Company's Board of Directors.
"Robert has brought leadership, direction and energy to the management of Kosan's overall business, built a reputation for integrity and openness within the investment community, and infused the management team and employees with a strong sense of motivation and purpose," said Peter Davis, Ph.D., Kosan's Chairman of the Board of Directors. "Today, Kosan is operating with a high degree of productivity, effectiveness and fiscal responsibility. The Board of Directors joins me in expressing confidence in Robert's management and the additional value he will bring to the Company as a Board member."
Dr. Johnson has served as Kosan's Chief Executive Officer since April 2006, having been named Acting Chief Executive Officer in February 2006. From April 2004 to February 2006, Dr. Johnson was Executive Vice President, Development, and Chief Medical Officer. From January 2002 to April 2004, Dr. Johnson served as Senior Vice President, Medical Affairs and Corporate Development, and in January 2003, he was also named Kosan's Chief Medical Officer. From September 2000 to January 2002, Dr. Johnson served as Vice President, Medical Affairs and Corporate Development. From 1998 to September 2000, Dr. Johnson was employed by Chiron Corporation, where he served as Vice President, Pharmacology and Preclinical Affairs through 1999 and as Vice President, Corporate Development. From 1991 to 1998, Dr. Johnson was Director of Pharmacology at Merck & Co., Inc. In addition, Dr. Johnson was a member of the faculty at the University of Pennsylvania from 1987 to 1991 and at Harvard Medical School from 1985 to 1987. Dr. Johnson received a B.A. and a Ph.D. in biophysics and an M.D. from the University of Pennsylvania.
Kosan Biosciences is a biotechnology company advancing two new classes of anticancer agents through clinical development -- Hsp90 (heat shock protein 90) inhibitors and epothilones. Kosan is leveraging its proprietary discovery platform to generate a pipeline of potentially significant product candidates, primarily in the area of oncology.
Hsp90 inhibitors have a novel mechanism of action targeting multiple pathways involved in cancer cell growth and survival. KOS-953 is Kosan's proprietary formulation of 17-AAG, a geldanamycin analog. The agent is currently in Phase I and II clinical trials, primarily for multiple myeloma and HER2-positive breast cancer. In addition, intravenous and oral formulations of Kosan's second-generation Hsp90 inhibitor, KOS-1022, are being evaluated in Phase I clinical trials.
Epothilones inhibit cell division with a mechanism of action similar to taxanes, one of the most successful classes of anti-tumor agents. KOS-862 is currently being studied in a Phase II single-agent clinical trial in patients with metastatic breast cancer, as well as a Phase II combination trial with Herceptin. KOS-1584, a second candidate designed to improve pharmacokinetics, is in Phase I clinical trials in patients with solid tumors. Kosan's
epothilone program is partnered with Roche through a global development and commercialization agreement.
For additional information on Kosan Biosciences, please visit the company's website at .
This press release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995 (the "Act"). Any statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. There are a number of important factors that could cause the results of Kosan to differ materially from those indicated by these forward- looking statements, including, among others, risks related to the clinical advancement of Kosan's clinical candidates, including the risk that clinical trials may not demonstrate safety and efficacy sufficient to obtain the requisite regulatory approvals or to result in a marketable product; and other risks detailed from time to time in the Company's SEC reports, including its Quarterly Report on Form 10-Q for the quarter ended March 31, 2006 and other periodic filings with the SEC. Kosan does not undertake any obligation to update forward-looking statements.
Kosan Biosciences Incorporated
CONTACT: Jane Green of Kosan Biosciences, +1-510-731-5335, or mobile,+1-510-652-4819, or firstname.lastname@example.org