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Menzella H.G.,Kosan Biosciences Inc. | Menzella H.G.,National University of Rosario | Carney J.R.,Kosan Biosciences Inc. | Carney J.R.,Solazyme | And 4 more authors.
Applied and Environmental Microbiology | Year: 2010

Recombinant microbial whole-cell biocatalysis is a valuable approach for producing enantiomerically pure intermediates for the synthesis of complex molecules. Here, we describe a method to produce polyketide intermediates possessing multiple stereogenic centers by combining chemobiosynthesis and engineered minipolyketide synthases (PKSs). Chemobiosynthesis allows the introduction of unnatural moieties, while a library of synthetic bimodular PKSs expressed from codon-optimized genes permits the Introduction of a variety of ketide units. To validate the approach, intermediates for the synthesis of irans-9,10-dehydroepothilone D were generated. The designer molecules obtained have the potential to greatly reduce the manufacturing cost of epothilone analogues, thus facilitating their commercial development as therapeutic agents. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Lancet J.E.,H. Lee Moffitt Cancer Center and Research Institute | Gojo I.,University of Maryland, Baltimore | Burton M.,H. Lee Moffitt Cancer Center and Research Institute | Quinn M.,University of Maryland, Baltimore | And 8 more authors.
Leukemia | Year: 2010

Heat shock protein 90 (Hsp90) is a molecular chaperone with many oncogenic client proteins. The small-molecule Hsp90 inhibitor alvespimycin, a geldanamycin derivative, is being developed for various malignancies. This phase 1 study examined the maximum-tolerated dose (MTD), safety and pharmacokinetic/ pharmacodynamic profiles of alvespimycin in patients with advanced acute myeloid leukemia (AML). Patients with advanced AML received escalating doses of intravenous alvespimycin (8-32 mg/m2), twice weekly, for 2 of 3 weeks. Dose-limiting toxicities (DLTs) were assessed during cycle 1. A total of 24 enrolled patients were evaluable for toxicity. Alvespimycin was well tolerated; the MTD was 24 mg/m2 twice weekly. Common toxicities included neutropenic fever, fatigue, nausea and diarrhea. Cardiac DLTs occurred at 32 mg/m2 (elevated troponin and myocardial infarction). Pharmacokinetics revealed linear increases in Cmax and area under the curve (AUC) from 8 to 32 mg/m2 and minor accumulation upon repeated doses. Pharmacodynamic analyses on day 15 revealed increased apoptosis and Hsp70 levels when compared with baseline within marrow blasts. Antileukemia activity occurred in 3 of 17 evaluable patients (complete remission with incomplete blood count recovery). The twice-weekly administered alvespimycin was well tolerated in patients with advanced AML, showing linear pharmacokinetics, target inhibition and signs of clinical activity. We determined a recommended phase 2 dose of 24 mg/m2. © 2010 Macmillan Publishers Limited All rights reserved.


Jhaveri K.,Sloan Kettering Cancer Center | Jhaveri K.,New York University | Miller K.,Indianapolis Cancer Center | Rosen L.,Premiere Oncology | And 9 more authors.
Clinical Cancer Research | Year: 2012

Purpose: We conducted a phase I dose-escalation study to define the maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics of alvespimycin (17-DMAG), a heat shock protein 90 (Hsp90) inhibitor, given in combination with trastuzumab. Experimental Design: Patients were treated with trastuzumab followed by intravenous alvespimycin on a weekly schedule. Hsp90 client proteins were measured at baseline and serially in peripheral blood lymphocytes (PBL) during cycle 1. Patients with advanced solid tumors progressing on standard therapy were eligible. Results: Twenty-eight patients (25, breast; 3, ovarian) were enrolled on to three dose cohorts: 60 (n = 9), 80 (n = 13), and 100 mg/m2 (n = 6). Dose-limiting toxicities (DLT) were: grade III left ventricular systolic dysfunction presenting as congestive heart failure in 1 patient (100 mg/m2), and reversible grade III keratitis in two patients (80 mg/m2). Drug-related grade III toxicity included one episode each of fatigue, diarrhea, myalgia, and back pain. Common mild to moderate toxicities included diarrhea, fatigue, myalgia, arthralgia, nausea, blurry vision, headache, back pain, and dry eyes. There was one partial response and seven cases of stable disease (range, 4-10 months), all inHER2+ MBC. In addition, an ovarian cancer patient had complete resolution of ascites and pleural effusion that lasted 24.8 months. There was no change in PK upon weekly dosing. Hsp70 effect continued to increase across four weeks and was most pronounced at 80 and 100 mg/m2. Conclusion: The combination of alvespimycin and trastuzumab is safe and tolerable at MTD. Antitumor activity was seen in patients with refractory HER2+ MBC and ovarian cancer. The recommended dose of alvespimycin for further study in this combination is 80 mg/m2 weekly. ©2012 AACR.


Lam E.T.,Ohio State University | Goel S.,Montefiore Einstein Center for Cancer Care | Schaaf L.J.,Ohio State University | Cropp G.F.,Kosan Biosciences Inc. | And 7 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2012

Purpose: First-in-man study of KOS-1584, a second generation epothilone. Methods: Patients with advanced solid malignancies received KOS-1584 every 3 weeks until disease progression. Using a modified Fibonacci dose escalation scheme, one patient was enrolled at each dose level until the first instance of grade 2 toxicity. Thereafter, a standard 3 + 3 design was utilized. Results: Sixty-six patients in 14 cohorts were dosed from 0.8 to 48 mg/m 2. Diarrhea, arthralgias, and encephalopathy were dose-limiting toxicities (DLTs) at doses ≥36 mg/m 2. At the recommended phase II dose (RP2D), the most common adverse effects were peripheral neuropathy (low grade), fatigue, arthralgias/myalgias, and diarrhea (31, 6%). The incidence of neutropenia was low. The overall clearance, volume of distribution, and half-life of KOS-1584 were 11 ± 6.17 L/h/m 2, 327 ± 161 L/m 2, and 21.9 ± 8.75 h, respectively. The half-life for the seco-metabolite (KOS-1891) was 29.6 ± 13.8 h. KOS-1584 exhibited linear pharmacokinetics. A dose-dependent increase in microtubulin bundle formation was observed at doses ≥27 mg/m 2. Two patients achieved partial responses and 24 patients had stable disease (SD). Conclusions: The RP2D of KOS-1584 is 36 mg/m 2. The lack of severe neurologic toxicity, diarrhea, neutropenia, or hypersensitivity reactions; favorable pharmacokinetic profile; and early evidence of activity support further evaluation. © 2011 Springer-Verlag.


Monk J.P.,Ohio State University | Villalona-Calero M.,Ohio State University | Larkin J.,Sloan Kettering Cancer Center | Otterson G.,Ohio State University | And 5 more authors.
Investigational New Drugs | Year: 2012

Purpose To determine the maximally tolerated dose (MTD) and pharmacokinetics of carboplatin plus KOS-862 (Epothilone D) a novel cytotoxic macrolide capable of causing mitotic arrest, in patients with advanced solid malignancies. Experimental Design Patients who have progressed on standard regimens were treated at four different levels of KOS-862(mg/m 2)/Carboplatin(AUC): 50/5,75/5, 75/6 and 100/6 in a "3+3" phase I study study design to determine MTD. Patients received KOS-862 on Days 1 and 8, and carboplatin on day 1, of 3-week cycles. Pharmacokinetics of KOS-862 and Carboplatin were studied. Results Twenty-seven patients enrolled in the study. At the top dose level, 2 out of the 9 patients experienced Dose Limiting Toxicity. (grade 3 peripheral motor neuropathy in both patients) Twenty-seven patients had sufficient plasma data points for pharmacokinetic analysis Both the parent drug, KOS-862, and the major inactive metabolite Seco-D KOS-862 (KOS-1965) were quantified in plasma. Kinetics of KOS-862 were the same as seen in monotherapy studies using the same route and time of administration. Two patients had tumor response after study treatment. Ten of 20 evaluable patients had stable disease after 2 cycles of study treatment. The MTD in the present study was KOS-862 100 mg/m 2 + carboplatin AUC=6. Conclusions The pharmacokinetics of KOS-862 were similar in this combination study to those seen in previous monotherapy studies using the same route and time of administration. We have described the MTD of this schedule. The neurotoxicity seen with this regimen should be considered prior to its administration in unselected populations. © Springer Science+Business Media, LLC 2011.


Yeh C.-H.,Quest Diagnostics Nichols Institute | Tseng R.,Quest Diagnostics Nichols Institute | Hannah A.,Kosan Biosciences Inc. | Estrov Z.,University of Texas M. D. Anderson Cancer Center | And 3 more authors.
Leukemia Research | Year: 2010

The heat shock protein 70 (HSP70) is one of the molecular chaperone family involved in the protection of cells upon exposure to various types of stresses. Plasma circulating HSP70 (cHSP70) is believed to play a role in the anti-tumor immune responses and its levels may reflect the levels of severity or the disease condition. Using electrochemiluminescence protein detection immunoassay, we measured the cHSP70 levels in the plasma of patients with acute myeloid leukemia (AML) (n=96), myelodysplastic syndrome (MDS) (n=28), and acute lymphoblastic leukemia (ALL) (n=40) and compared with those in normal individuals (n=99). cHSP70 levels were significantly higher in AML (median: 10.71. ng/mL, range: 1.93-79.0. ng/mL) and ALL (median: 27.59. ng/mL, range: 5.09-129.6. ng/mL) as compared to those in MDS (median: 4.54. ng/mL, range: 1.35-58.3. ng/mL) or healthy controls (median: 4.13. ng/mL, range: 1.75-13.6. ng/mL). Levels of cHSP70 showed significant positive correlation with lactate dehydrogenase (LDH) and white blood cells (WBC) in AML and ALL patients, which may reflect overall tumor load. Furthermore, patients with higher levels of cHSP70 had significantly shorter survival in AML (P=0.04) and ALL (P=0.05), suggesting that in these two acute diseases, cHSP70 is an indicator for poor prognosis. Our data support the potential of using free cHSP70 as a biomarker in leukemias and potentially other types of cancers. © 2009 Elsevier Ltd.


Useglio M.,National University of Rosario | Peiru S.,National University of Rosario | Rodriguez E.,National University of Rosario | Labadie G.R.,National University of Rosario | And 3 more authors.
Applied and Environmental Microbiology | Year: 2010

In vivo reconstitution of the TDP-L-megosamine pathway from the megalomicin gene cluster of Micromonospora megalomicea was accomplished by the heterologous expression of its biosynthetic genes in Escherichia coli. Mass spectrometric analysis of the TDP-sugar intermediates produced from operons containing different sets of genes showed that the production of TDP-L-megosamine from TDP-4-keto-6-deoxy-D-glucose requires only five biosynthetic steps, catalyzed by MegBVI, MegDII, MegDIII, MegDIV, and MegDV. Bioconversion studies demonstrated that the sugar transferase MegDI, along with the helper protein MegDVI, catalyzes the transfer of L-megosamine to either erythromycin C or erythromycin D, suggesting two possible routes for the production of megalomicin A. Analysis in vivo of the hydroxylation step by MegK indicated that erythromycin C is the intermediate of megalomicin A biosynthesis. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Liu Y.,Kosan Biosciences Inc. | Carreras C.W.,Kosan Biosciences Inc. | Claypool M.,Kosan Biosciences Inc. | Myles D.C.,Kosan Biosciences Inc. | Shaw S.J.,Kosan Biosciences Inc.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

The role of the erythromycin 4″-hydroxyl group has been explored on the motilin agonist potential in the 9-dihydroerythromycin series of motilides. The compounds show potencies 2- to 4-fold superior to the corresponding hydroxylated compounds. The relationship is maintained when the 9-hydroxyl is alkylated to generate the corresponding 4″-deoxy-9-O-acetamido-9- dihydroerythromycins. However, concomitant with this increase in potency is an increase in hERG inhibition. © 2011 Elsevier Ltd. All rights reserved.


Please join us for WIB-San Francisco Bay Area’s “Negotiating Through Career Goals, Leveraging Skills for a Win/Win Situation” — the third and final Meet the Experts event in our 2013 Entrepreneur Series. Linda Amuso, Barbara Preston, and Dorian Hirth will serve on a moderated panel discussing essential negotiation skills in the work environment to create a win/win situation, especially as they relate to career changes. Learn how best to market your personal brand and articulate your achieved goals as you move on to new opportunities. Our panel of experts will discuss: · Negotiating offers, promotions, deals and opportunities · Understanding a total compensation package · Conflict resolution versus negotiations: understanding which battles to fight and which to let go · Knowing your worth: what to ask for, what to give up · Best way to leverage your brand to get your ultimate goal Members and non-members are invited to network and meet other professionals, and hear the panelists share their insights, especially as they relate to the bioscience industry. So bring your questions and “Meet the Experts!” As always, men are welcome. Linda Amuso is President at Radford. She is a highly recognized thought-leader and an expert in the field of executive and employee compensation design for the technology and life sciences industries. For 25 years, Linda has worked directly with senior management and Boards of Directors on developing and implementing executive, incentive and equity strategies while navigating the ever changing governance landscape. Since joining Radford in 2005, Linda has been instrumental in building Radford’s consulting business and expanding Radford’s services globally. Dr. Barbara Preston made the transition to her current role as a scientific “talent scout” after many years as a research scientist. She obtained her BS and MS in Microbiology at the University of Maryland, learned molecular biology at NIH, and earned her Ph.D. in Pharmacology at Cornell University. Subsequently Dr. Preston did her postdoc with Palmer Taylor, then Chair of UCSD’s Department of Pharmacology, looking at neuronal differentiation of stem-like cells. However, the opportunity to recruit executive management and scientists in the biomedical field combined her love for both science and people and she joined a national recruiting firm to build their scientific office. Within four years she billed and collected $1 Million for her employer through successful placements. In 2003 she stepped out in faith and co-founded PharmaScouts, Inc. where she continues attracting top talent for biomedical companies. PharmaScouts is a WBENC certified woman-owned business and Dr. Preston is an active member of several scientific, professional, and volunteer organizations. She has served as an executive and board member for San Diego’s Association for Women in Science and is currently a board member for a local nonprofit combatting homelessness. Dorian Hirth is Senior Vice President, Human Resources and Facilities Operations at Nektar Therapeutics. Ms. Hirth is responsible for designing and implementing HR strategies and programs that attract, develop and retain talent for a high-performing workforce. Ms. Hirth’s experience spans 20 years at biotechnology companies leading strategic and tactical aspects of human resource functions, including managing issues surrounding mergers and acquisitions. In addition, she served as Vice President, Human Resources and Facilities at Kosan Biosciences and Corgentech/Anesiva.

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