Publications by authors named "Timothy B Lowinger"

12 Publications

  • Page 1 of 1

Antibody drug conjugates for treatment of breast cancer: Novel targets and diverse approaches in ADC design.

Pharmacol Ther 2018 01 27;181:126-142. Epub 2017 Jul 27.

Mersana Therapeutics, Cambridge, MA 02139, United States.

Breast cancer is a heterogeneous group of malignancies with a spectrum of molecular subtypes, pathologies and outcomes that together comprise the most common non-cutaneous cancer in women. Currently, over 80% of breast cancer patients are diagnosed at relatively early stages of disease where there are encouraging data on outcomes and long term survival. However, there is currently no curative option for those patients with metastatic disease and there is a substantial medical need to identify effective and safe treatment options for these patients. One approach to improve cancer therapy is by designing therapeutics directed against targets with differential levels of expression on malignant versus normal cells with the goal of improving tumor selectivity and reducing damage to normal tissues. Antibody drug conjugates (ADCs) are a rapidly evolving therapeutic class that exploits the target-selectivity of monoclonal antibodies (MAbs) to deliver cytotoxic drugs to antigen-expressing cells (Lambert & Morris, 2017; Senter, 2009; Thomas, Teicher, & Hassan, 2016; Trail, 2013). The regulatory approval of ADCs for both hematologic malignancies (brentuximab vedotin) (Younes et al., 2010) and solid tumors (ado-trastuzumab emtansine) (Amiri-Kordestani et al., 2014; Verma et al., 2012) clearly demonstrates the clinical potential of ADCs. This review will focus on targets under consideration for breast cancer directed ADCs and on the technology modifications being considered to improve ADC efficacy and safety.
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http://dx.doi.org/10.1016/j.pharmthera.2017.07.013DOI Listing
January 2018

A Polymer-Based Antibody-Vinca Drug Conjugate Platform: Characterization and Preclinical Efficacy.

Cancer Res 2015 Aug 25;75(16):3365-72. Epub 2015 Jun 25.

Mersana Therapeutics, Inc., Cambridge, Massachusetts.

Antibody-drug conjugates (ADC) are an emerging drug class that uses antibodies to improve cytotoxic drug targeting for cancer treatment. ADCs in current clinical trials achieve a compromise between potency and physicochemical/pharmacokinetic properties by conjugating potent cytotoxins directly to an antibody at a 4:1 or less stoichiometric ratio. Herein, we report a novel, polyacetal polymer-based platform for creating ADC that use poly-1-hydroxymethylethylene hydroxymethyl-formal (PHF), also known as Fleximer. The high hydrophilicity and polyvalency properties of the Fleximer polymer can be used to produce ADC with high drug loading without compromising physicochemical and pharmacokinetic properties. Using trastuzumab and a vinca drug derivative to demonstrate the utility of this platform, a novel Fleximer-based ADC was prepared and characterized in vivo. The ADC prepared had a vinca-antibody ratio of 20:1. It exhibited a high antigen-binding affinity, an excellent pharmacokinetic profile and antigen-dependent efficacy, and tumor accumulation in multiple tumor xenograft models. Our findings illustrate the robust utility of the Fleximer platform as a highly differentiated alternative to the conjugation platforms used to create ADC currently in clinical development.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-0129DOI Listing
August 2015

Pharmacokinetics and antitumor efficacy of XMT-1001, a novel, polymeric topoisomerase I inhibitor, in mice bearing HT-29 human colon carcinoma xenografts.

Clin Cancer Res 2012 May 5;18(9):2591-602. Epub 2012 Mar 5.

Division of Pharmacotherapy & Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

Purpose: To evaluate the pharmacokinetics and tissue disposition of macromolecular camptothecin (CPT) drug conjugate, XMT-1001, and irinotecan (CPT-11) in mice bearing HT-29 xenograft tumors.

Experimental Design: The antitumor efficacy of XMT-1001 was evaluated in the mouse HT-29 human colon carcinoma xenograft model. XMT-1001 was administered intravenously to female athymic nude (nu/nu) mice bearing established HT-29 xenograft tumors (n = 10) at 15, 30, and 60 mg CPT equivalents/kg on weekly or biweekly schedules. The tumor growth inhibition and tumor growth delay endpoints were used for efficacy evaluation. In the pharmacokinetic study, XMT-1001 was administered intravenously at a pharmacologically relevant dose of 60 mg CPT equivalents/kg × 1 via tail vein or an equimolar dose of CPT-11 at 100 mg/kg i.p. × 1. Mice (n = 3 per time point) were euthanized from 0.083 to 336 hours after XMT-1001 administration and from 0.083 to 24 hours after CPT-11. Plasma, tumor, and tissues were collected from all animals. A liquid chromatography-tandem mass spectrometry assay was used to measure XMT-1001, conjugate release products, CPT-20-O-(N-succinimido-glycinate; CPT-SI) and CPT-20-O-(N-succinamidoyl-glycinate; CPT-SA), and CPT.

Results: After XMT-1001 administration, the majority of the plasma exposure is accounted for by conjugated CPT. XMT-1001 exhibited a prolonged exposure of conjugated drug, active conjugate primary release products, CPT-SI and CPT-SA, and active CPT, which was associated with greater antitumor response compared with CPT-11.

Conclusions: XMT-1001 provides an extended systemic and tumor exposure of conjugated drug and shows improved antitumor effect compared with CPT-11.
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http://dx.doi.org/10.1158/1078-0432.CCR-11-1554DOI Listing
May 2012

Naphthol derivatives as TRPV1 inhibitors for the treatment of urinary incontinence.

Bioorg Med Chem Lett 2011 Jun 9;21(11):3354-7. Epub 2011 Apr 9.

Research Center Kyoto, Bayer Yakuhin, Ltd, Kizu, Soraku, Kyoto 619-0216, Japan.

We have identified naphthol derivatives as inhibitors of the vanilloid receptor TRPV1 by high throughput screening. The initial lead showed high clearance in rats and has been optimized by enhancing the acidity of the phenol group. Compound 6b has reduced clearance, improved potency and is active in rat cystometry models of urinary incontinence after intravenous administration.
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http://dx.doi.org/10.1016/j.bmcl.2011.04.013DOI Listing
June 2011

Recent developments in the discovery of protein kinase inhibitors from the urea class.

Curr Opin Drug Discov Devel 2004 Sep;7(5):600-16

Bayer Research Center, Bayer Pharmaceutical Corporation, West Haven, CT 06516, USA.

With two compounds on the market (Gleevec and Iressa), and a number of drug candidates in late-stage clinical trials, small-molecule kinase inhibitors hold great potential as novel therapies for cancer and inflammatory disorders. Inhibitors from the urea class were first reported in 1996 and have emerged as an important compound class for medicinal chemists due to their unique binding mode and kinase inhibition profile. Currently, five members of this class are undergoing clinical trials, BIRB-796 (Boehringer Ingelheim Pharmaceuticals Inc), BAY-43-9006 (Bayer AG/Onyx Pharmaceuticals Inc), CP-547632 (Pfizer Inc), MLN-518 (Millennium Pharmaceuticals Inc) and KRN-951 (Kirin Brewery Co Ltd). This review focuses on the most recent developments in the discovery of urea-based protein kinase inhibitors.
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September 2004

Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 3: Orally active anti-inflammatory agents.

Bioorg Med Chem Lett 2004 Aug;14(15):4019-22

Department of Chemistry, Research Center Kyoto, Bayer Yakuhin Ltd., Kizu, Soraku, Kyoto 619-0216, Japan.

A series of 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives was synthesized and evaluated as I kappaB kinase beta (IKK-beta) inhibitors. Modification of a novel IKK-beta inhibitor 1 (IKK-beta IC(50)=1500 nM, Cell IC(50)=8000 nM) at the 4-phenyl ring and 6-phenol group on the pyridine core ring resulted in a marked increased in biological activities. An optimized compound, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile, exhibited excellent in vitro profiles (IKK-beta IC(50)=8.5 nM, Cell IC(50)=60 nM) and a strong oral efficacy in in vivo anti-inflammatory assays (significant effects at 1mg/kg, po in arachidonic acid-induced ear edema model in mice).
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http://dx.doi.org/10.1016/j.bmcl.2004.05.041DOI Listing
August 2004

Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 2: Improvement of in vitro activity.

Bioorg Med Chem Lett 2004 Aug;14(15):4013-7

Department of Chemistry, Research Center Kyoto, Bayer Yakuhin Ltd., Kizu, Soraku, Kyoto 619-0216, Japan.

A series of 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives was synthesized and evaluated as IkappaB kinase beta (IKK-beta) inhibitors. Substitution of an aminoalkyl group for the aromatic group at the 4-position on the core pyridine ring resulted in a marked increase in both kinase enzyme and cellular potencies, and provided potent IKK-beta inhibitors with IC(50) values of below 100 nM.
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http://dx.doi.org/10.1016/j.bmcl.2004.05.040DOI Listing
August 2004

Omega-carboxypyridyl substituted ureas as Raf kinase inhibitors: SAR of the amide substituent.

Bioorg Med Chem Lett 2004 Feb;14(3):783-6

Department of Chemistry Research, Bayer Research Center, 400Morgan Lane, West Haven, CT 06516, USA.

Bis-aryl ureas have been disclosed previously as a potent class of Raf kinase inhibitors. Modifications in the amide portion led to an improvement in aqueous solubility, an important characteristic for an oral drug. Based on this finding, we hypothesize that this portion of the molecule is directed towards the solvent in Raf-1.
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http://dx.doi.org/10.1016/j.bmcl.2003.11.041DOI Listing
February 2004

Discovery of novel and selective IKK-beta serine-threonine protein kinase inhibitors. Part 1.

Bioorg Med Chem Lett 2003 Mar;13(5):913-8

Department of Chemistry, Research Center Kyoto, Bayer Yakuhin, Ltd., Kizu, Soraku, Kyoto 619-0216, Japan.

IkappaB kinase beta (IKK-beta) is a serine-threonine protein kinase critically involved in the activation of the transcription factor Nuclear Factor kappa B (NF-kappaB) in response to various inflammatory stimuli. We have identified a small molecule inhibitor of IKK-beta. Optimization of the lead compound resulted in improvements in both in vitro and in vivo potency, and provided IKK-beta inhibitors exhibiting potent activity in an acute cytokine release model (LPS-induced TNFalpha).
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http://dx.doi.org/10.1016/s0960-894x(02)01046-6DOI Listing
March 2003

Design and discovery of small molecules targeting raf-1 kinase.

Curr Pharm Des 2002 ;8(25):2269-78

Bayer Research Center, Bayer Corporation, Pharmaceutical Division, 400 Morgan Lane, West Haven, CT 06516, USA.

Raf kinase, an enzyme which acts downstream in the Ras signaling pathway, is involved in cancerous cell proliferation. Thus, small molecule inhibitors of Raf kinase activity may be important agents for the treatment of cancer. A novel class of Raf-1 inhibitors was discovered, using a combination of medicinal and combinatorial chemistry approaches. This effort culminated in the identification of the clinical candidate BAY 43-9006, currently undergoing Phase I clinical trials. The present review summarizes the medicinal chemistry development of ureas as highly potent inhibitors of Raf-1 kinase.
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http://dx.doi.org/10.2174/1381612023393125DOI Listing
March 2003

Definition of Several Control Elements Relevant to the Stereodefined Serial Elaboration of Belted Poly(spirotetrahydrofurans) Fitted with a Cyclohexane Core.

J Org Chem 1996 Oct;61(21):7492-7507

Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210.

The stereochemistry of the condensations of 2-cyclohexenones, alpha-arylidenecyclohexanones, and alpha-(tert-butyldimethylsiloxy)cyclohexanones carrying one or two (both syn and anti) spirotetrahydrofuran units adjacent to the carbonyl with allyl organometallics (especially indium) and with the Normant reagent (ClMgO(CH(2))(3)MgCl) is described. Good levels of anti stereoselection are observed in the alpha-arylidene series. Subsequent cyclization generates a second (or third) tetrahydrofuran ring possessing trans vicinal oxygens. Useful levels of matched and mismatched diastereoselection are also attainable by prior alpha-oxygenation. The intrinsic differences in diastereomer production between indium and magnesium organometallics are highlighted. A clear distinction regarding the anticipated direction of stereoselectivity is made on the grounds of chelation capabilities and the intra- or intermolecularity of carbon-carbon bond formation. Finally, the two protocols that are described in detail are shown to be iterative, a feature that augurs well for ultimately accessing the eight possible hexaspirocyclohexanes in an efficient and stereocontrolled manner.
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http://dx.doi.org/10.1021/jo960962hDOI Listing
October 1996

trans,anti,trans-Tetra(spirotetrahydrofuranyl)cyclohexane-1,2-dione. Stereocontrolled Synthesis and Definition of Its Susceptibility to Photoisomerization.

J Org Chem 1996 Oct;61(21):7486-7491

Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210.

The title alpha-diketone (18) has been synthesized in stereocontrolled fashion. The ability to introduce the four contiguous spirocyclic ether oxygens in extended trans fashion rests on the ability of the Normant reagent (ClMgCH(2)CH(2)CH(2)OMgCl) to engage in chelation control during 1,2-addition to an alpha-oxy substituted cyclohexanone. The successful pathway is dependent on the ability of osmium tetraoxide to add (slowly) across the double bond of the cyclohexene precursor. The highly substituted 1,2-cyclohexanedione is quite sensitive to light and rearranges by means of an interesting photoisomerization process to a laterally fused pyran system. A likely mechanistic pathway for this intramolecular isomerization is presented.
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http://dx.doi.org/10.1021/jo960961pDOI Listing
October 1996