After completing the course, the reader will be able to:1. Educate community oncologists about the promise of anti-CTLA-4 monoclonal antibodies for the treatment of advanced cancer. 2. Suggest that CTLA-4 blockade overcomes barriers to effective immunotherapy for cancer. 3. Describe the rational design and clinical development strategy taken with the CTLA-4 antagonist tremelimumab.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACT

1 UK-78,282, a novel piperidine blocker of the T lymphocyte voltage-gated K + channel, Kv1.3, was discovered by screening a large compound ®le using a high-throughput 86 Rb e ux assay. This compound blocks Kv1.3 with a IC 50 of *200 nM and 1 : 1 stoichiometry. A closely related compound, 325, containing a benzyl moiety in place of the benzhydryl in UK-78,282, is signi®cantly less potent. 2 Three lines of evidence indicate that UK-78,282 inhibits Kv1.3 in a use-dependent manner by preferentially blocking and binding to the C-type inactivated state of the channel. Increasing the fraction of inactivated channels by holding the membrane potential at 750 mV enhances the channel's sensitivity to 282. Decreasing the number of inactivated channels by exposure to *160 mM external K + decreases the sensitivity to UK-78,282. Mutations that alter the rate of Ctype inactivation also change the channel's sensitivity to UK-78,282 and there is a direct correlation between t h and IC 50 values.3 Competition experiments suggest that UK-78,282 binds to residues at the inner surface of the channel overlapping the site of action of verapamil. Internal tetraethylammonium and external charybdotoxin do not compete UK-78,282's action on the channel. 4 UK-78,282 displays marked selectivity for Kv1.3 over several other closely related K + channels, the only exception being the rapidly inactivating voltage-gated K + channel, Kv1.4. 5 UK-78,282 e ectively suppresses human T-lymphocyte activation.

Purine-based analogs of SDZ 211-500 (5) were prepared and evaluated as inactivation modifiers of guinea pig or human cardiac sodium (Na) channels expressed in Xenopus oocytes. Substances which remove or slow the Na channel inactivation process in cardiac tissue are anticipated to prolong the effective refractory period and increase inotropy and thus have potential utility as antiarrhythmic agents. Heterocyclic substitution at the 6-position of the purine ring resulted in compounds with increased Na activity and potency, with 5-membered heterocycles being optimal. Only minor modifications to the benzhydrylpiperazine side chain were tolerated. Selected compounds which delayed the inactivation of Na channels were found to increase refractoriness and contractility in a rabbit Langendorff heart model, consistent with the cellular mechanism. Activity in both the oocyte and rabbit heart assays was specific to the S enantiomers. Preliminary in vivo activity has been demonstrated following intravenous infusion. The most promising compound on the basis of in vitro data is the formylpyrrole (S)-74, which is 25-fold more potent than DPI 201-106 (1) in the human heart Na channel assay.

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