Retinoic acid (RA) is the major clinically useful therapy for two leukemias, acute promyelocytic leukemia (APL) and juvenile myelomonocytic leukemia (JMML). In APL, all-trans-RA induces complete remission in most patients, but relapse is common due to the rapid development of RA resistance and induction of RA toxicity. Agents which are more effective and do not lead to resistance are needed. Some children with JMML are stabilized with 13-cis-RA until they can receive bone marrow transplants at an older age, but more effective agents are needed to extend stabilization to a larger percentage of patients. This project will develop new retinoids that are more effective than RA for the therapy of APL and JMML. The new drugs will be derived from a unique class of retinoids that were developed at UAB by the investigator and co-investigator of this application. Two UAB8 isomers from this class were shown to be more effective than RA in an APL model and as effective as RA in a JMML model, yet they were less toxic and exhibited a more favorable pharmacological profile. They will first explore more fully the activity of UAB8 and then we will optimize the structure of UAB retinoids to provide the best clinical candidates for APL and JMML therapy. To accomplish this goal, a team of scientists with backgrounds in retinoid research has been assembled, including medicinal chemists, clinical oncologists, biochemists, pharmacologists. This team will use a broadly based approach involving a) synthesis; b) nuclear receptor binding/transactivational assays; c) in vitro assays (induction of differentation and/or apoptosis in APL cells, and inhibition of murine and human JMML colony formation; d) pharmacology studies on the self-induction of metabolism in mice and e) in vivo evaluation in a JMML mouse model.
| Atigadda, Venkatram R; Vines, Kimberly K; Grubbs, Clinton J et al. (2003) Conformationally defined retinoic acid analogues. 5. Large-scale synthesis and mammary cancer chemopreventive activity for (2E,4E,6Z,8E)-8-(3',4'-dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid (9cUAB30). J Med Chem 46:3766-9 |
