Structure–activity relationships of methylene or terminal side chain modified retinoids on the differentiation and cell death signaling in NB4 promyelocytic leukemia cells Diana Ivanova, a Aur elie Rossin, a Hinrich Gronemeyer, a, * Alain Valla, b Dominique Cartier, b R egis Le Guillou b and Roger Labia b a Institut de G en etique et de Biologie Mol eculaire et Cellulaire, 1 rue Laurent Fries, BP 10142, 67404 Illkirch, France b Laboratoire de Chimie et Biologie des Substances Naturelles, 6 rue de l’Universit e, 29000 Quimper, France Received 12 January 2004; revised 12 May 2004; accepted 3 June 2004 Available online 26 June 2004 Abstract—New structure–activity relationships of a series of methylene or side chain modified retinoids on NB4 acute promyelocytic leukemia cells are investigated. The differentiation- and apoptosis-inducing potential of these compounds is analyzed on the basis of their selective retinoic acid receptor binding profile. Ó 2004 Elsevier Ltd. All rights reserved. Retinoids are powerful signaling compounds that regu- late a plethora of physiological processes during embryogenesis, organogenesis, and in adult organ homeostasis. Due to their differentiation- and apoptosis- inducing activities they are used as therapeutic agents for the treatment of several diseases. Most notably ret- inoids display a strong cancer therapeutic and cancer preventive activity. 1 The pleiotropic effects of retinoic acid (RA) analogs are mediated by RAR (retinoic acid receptor) and RXR (retinoid X receptor), which belong to the nuclear receptor superfamily of transcription factors. RAR and RXR bind as heterodimers on the promoter region of retinoic acid target genes to modulate their expression. All three RARs (a, b, cÞ are activated by all-trans reti- noic acid (ATRA) and 9-cis RA whereas RXRs (a, b, c) bind efficiently 9-cis RA. 2 There is evidence that RXRs may have alternative ligands 3 and that ATRA may bind to certain ‘orphan’ nuclear receptors. 4 Remarkable progress has been made in the past few years on the understanding of the molecular basis of the biological activities, including the cancer therapeutic potential, of retinoids and the cognate receptors. In the case of APL (acute promyelocytic leukemia) the com- bination of ATRA and chemotherapy induces a com- plete remission in more than 70% of the treated patients. A t(15,17) chromosomal translocation generating a fusion protein between RARa and PML is at the origin of the pathology. The molecular action(s) of the PML–RARa fusion protein and the effect of RA ?tul> are reasonably well understood. 5 Compared to RARa, PML–RARa recruits more efficiently nuclear co-repressors (N-CoRs), which are part of a complex including histone deacetylases (HDACs). Accumulation of these factors at the promoters of retinoic acid- responsive genes leads to transcriptional repression that a physiological concentration of ATRA cannot relieve. This results in a block of differentiation of myeloid progenitor cells at the promyelocytic stage. In addition, the oncogenic potential of the fusion protein can also originate from altered PML functions and distinct interaction profiles with itself and/or other key regula- tory factors relative to wild-type PML or RARa. High concentrations of ATRA cause a release of the tran- scriptional repressor complexes, which restores the ‘normal’ retinoic acid and PML programs. ATRA therapy of APL patients has a number of com- plications; one is that patients can acquire resistance due Keywords: Retinoids; Rexinoids; RAR selectivity; Leukemia; Differ- entiation; Apoptosis. * Corresponding author. Tel.: +33-388653473; fax: +33-388653201; e-mail: hg@igbmc.u-strasbg.fr 0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2004.06.002 Bioorganic & Medicinal Chemistry Letters 14 (2004) 4257–4261