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WEDNESDAY, NOVEMBER 4
7:30 am Continental Breakfast Breakout Discussions
8:35 Chairperson’s Remarks
8:40 Structure-Guided Design of AP24534, a Potent Orally Active Inhibitor BCR-ABLT315I and other Resistant Mutants
William Shakespeare, Ph.D., Vice President, Drug Discovery, ARIAD Pharmaceuticals, Inc.
Resistance to the BCR-ABL kinase inhibitor imatinib in patients with chronic myeloid leukemia (CML) is associated with emergence of BCR-ABL point mutations that preclude effective drug binding. Although most mutants are inhibited with the second-line therapies dasatinib and nilotinib, neither compound inhibits the T315I mutant which represents approximately 15-20% of all clinically observed mutants. Here, we report the pre-clinical evaluation of AP24534, a potent, orally active inhibitor of BCR-ABLT315I and other resistant mutants. AP24534 inhibited all tested BCR-ABL mutants in cellular and biochemical assays, suppressed BCR-ABLT315I-driven tumor growth in mice, and completely abolished resistance in cell-based mutagenesis screens. This work supports evaluating AP24534 as a pan-BCR-ABL inhibitor for the treatment of CML.
9:10 Cellular Target Profiling and Quantitative Phosphoproteomics Reveal Insight into a Drug’s Efficiency and Cellular Mode of Action 
Jutta Fritz, Ph.D., Head, Technology and Business Development, KINAXO Biotechnologies
Multi-targeted kinase inhibitors have emerged as promising anti-cancer drugs. Due to their broad selectivity, it is particularly challenging to understand their mode of action in a cellular context. Therefore, system-wide approaches integrating drug target identification and global phosphoproteome analysis are essential to gain insight into the inhibitor’s impact on signal transduction. A comprehensive approach using chemical proteomics and quantitative phosphoproteomics reveals a drug’s target profile and allows quantification of phosphorylation patterns in relation to drug administration. This approach allows monitoring of the integration of signaling and might predict potential side effects and point to additional therapeutic applications.
9:40 The Discovery and Optimization of Highly Selective p38 Inhibitors
Martha J. Kelly, Ph.D., Senior Director, Chemistry, Locus Pharmaceuticals
The mitogen-activated protein (MAP) kinase p38alpha plays an important role in regulating several pro-inflammatory cytokines, and inhibition of this target has been extensively studied as a means of treating diseases such as rheumatoid arthritis and inflammatory bowel disease. Using the Locus virtual fragment-based drug design technology, a novel series of p38a inhibitors was identified that bind to the DFG-out form of the protein and that do not have a direct interaction with the hinge. These compounds have excellent kinase and cell potency, and are extremely selective inhibitors of p38a.
10:10 Networking Coffee Break in the Exhibit Hall
10:55 CX-4945, a First in Class Selective Inhibitor of CK2, Effectively Blocks Multiple CK2-Mediated Signaling Pathways, including Akt, and Demonstrates Significant Antiproliferative and Antitumor Activities
Kenna Anderes, Ph.D., Vice President, Cancer Biology, Cylene Pharmaceuticals
CK2 overexpression is well documented in many cancers and represents a previously unexploited molecular target. CX-4945 is a potent, selective inhibitor of CK2 and modulates key survival pathways in cancer cells including specific inhibition of Akt signaling. CX-4945 has broad therapeutic potential in common cancers as well as in niche indications and has advanced rapidly into Phase I clinical trials.
11:25 Cediranib: a New and Potent Pan-VEGFR Tyrosine Kinase Inhibitor that is Active in Multiple Tumor Types
Ursula A. Matulonis, M.D., Assistant Professor, Medicine, Harvard Medical School, Dana-Farber Cancer Institute
11:55 Development of an Antibody Drug Conjugate Targeting The EphA2 Receptor Tyrosine Kinase
Dowdy Jackson, Ph.D., Scientist, MedImmune
EphA2 is a member of one of the largest family of receptor tyrosine kinases and is highly expressed during embryogenesis and is involved in neuronal guidance. In normal adult tissues, the expression of EphA2 is low and limited to a few tissues. The expression of EphA2 is upregulated in many human cancers, including ovarian, prostate and breast cancers, and is often associated with poor patient prognosis. The high level of EphA2 expression in tumors, the correlation with poor patient prognosis and the low level of expression in normal adult tissues makes EphA2 an attractive target for cancer therapy. We have conjugated the microtubule inhibitor monomethylauristatin F (MMAF) to a human IgG1 anti-EphA2 antibody (1C1) using the maleimidocaproyl (mc) linker. The anti-EphA2-mcMMAF antibody conjugate (1C1-mcMMAF) is internalized resulting in the intracellular release of MMAF and the inhibition of tumor cell growth through the induction of caspase3-dependent apoptosis. Our EphA2 antibody drug conjugate inhibits the growth of several EphA2 expressing tumors in xenograft models in vivo without significant adverse effects. Our data supports the use of an antibody drug conjugate approach to target and inhibit the growth of EphA2 expressing tumors.
12:25 pm Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own
1:55 Chairperson’s Remarks
2:00 Targeting Bruton’s Tyrosine Kinase
Lee Honigberg, Ph.D., Director, Cancer Biology, Pharmacyclics
2:30 Know Pain, Know Gain: Development of a Selective Epsilon PKC Inhibitor for the Treatment of Pain
James Tomlinson, Ph.D., Associate Scientific Director, Molecular and Integrative Pharmacology, KAI Pharmaceuticals, Inc.
KAI pharmaceuticals had developed a potent and selective inhibitor of epsilon PKC that completely reverses allodynia and hyperalgesia in multiple models of neuropathic and inflammatory pain. The development candidate, KAI-1678 has proven to be safe and well tolerated in phase 1 clinical trials and is currently being tested in three phase 2 trials in neuropathic and post-operative pain. We will describe the properties of this novel class of inhibitor and its potential to be the first molecule in this class of promising new pain therapeutics with general applicability.
KAI pharmaceuticals had developed a potent and selective inhibitor of epsilon PKC that completely reverses allodynia and hyperalgesia in multiple models of neuropathic and inflammatory pain. The development candidate, KAI-1678 has proven to be safe and well tolerated in phase 1 clinical trials and is currently being tested in three phase 2 trials in neuropathic and post-operative pain. We will describe the properties of this novel class of inhibitor and its potential to be the first molecule in this class of promising new pain therapeutics with general applicability.
3:00 Networking Ice Cream Refreshment Break in Exhibit Hall (Last Chance for Viewing)
3:40 Targeting Diabetes
Alan R. Saltiel, Ph.D., Mary Sue Coleman Director, Life Sciences Institute; John Jacob Abel Professor, Internal Medicine and Physiology, Life Sciences Institute, University of Michigan
Obesity is associated with chronic low-grade inflammation that negatively impacts insulin sensitivity. High fat diet can increase NFκB activation in mice, which leads to a sustained elevation in level of IκB kinase ε (IKKε) in liver, adipocytes and adipose tissue macrophages. IKKε knockout mice are protected from high fat diet-induced obesity, chronic inflammation in liver and fat, hepatic steatosis and whole-body insulin resistance. These mice show increased energy expenditure and thermogenesis on high fat diet compared to wild type mice. They maintain insulin sensitivity in liver and fat, without activation of the proinflammatory JNK pathway associated with obesity. Gene expression analyses indicate that targeted deletion of IKKε increases expression of the uncoupling protein UCP1, reduces expression of inflammatory cytokines, and changes expression of certain regulatory proteins and enzymes involved in glucose and lipid metabolism. Thus, IKKε may represent an attractive new therapeutic target for obesity, insulin resistance, diabetes and other complications associated with these disorders.
4:10 Targeting Protein Kinases in CNS Discovery
D. Martin Watterson, Ph.D., J.G. Searle Professor & Co Director, Center for Drug Discovery & Chemical Biology, Northwestern University
Although discovery research has identified a variety of potential CNS targets, the development of kinase-targeted therapies for CNS diseases has lagged behind that of peripheral tissue disorders. This is due mainly to the special challenges, such as effective brain penetrance, presented by CNS drug discovery that are in addition to the standard ADMET considerations. The presentation will provide an overview of issues confronting the targeting of CNS protein kinases, using case studies to demonstrate how the field is leveraging early stage drug discovery approaches to better anticipate later stage barriers to project success.
4:40 A Successful Paradigm for Kinase Inhibitor Therapy: Advances in Treatment of Renal Cell Carcinoma
M. Dror Michaelson, M.D., Ph.D., Massachusetts General Hospital Cancer Center
The tumor suppressor Von-Hippel Lindau (VHL) gene is mutated in most cases of RCC resulting in high-level expression of VEGF and other proteins. Anti-VEGF receptor therapy with multi-targeted inhibitors such as sunitinib and sorafenib has revolutionized treatment of advanced RCC. The serine-threonine kinase Mammalian Target of Rapamycin (mTOR) is a second validated therapeutic target in RCC. Ongoing studies are evaluating the combinatorial use of kinase inhibitors in a continued effort to improve rationally targeted therapy of this disease.
5:10 Close of Conference
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