Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2) Joey L. Methot, a, * Prasun K. Chakravarty, d Melissa Chenard, c Joshua Close, a Jonathan C. Cruz, c William K. Dahlberg, a Judith Fleming, b Christopher L. Hamblett, a Julie E. Hamill, a Paul Harrington, a,  Andreas Harsch, a Richard Heidebrecht, a Bethany Hughes, a Joon Jung, a Candia M. Kenific, c Astrid M. Kral, b Peter T. Meinke, d Richard E. Middleton, a Nicole Ozerova, b David L. Sloman, a Matthew G. Stanton, a Alexander A. Szewczak, a Sriram Tyagarajan, d David J. Witter, a J. Paul Secrist b and Thomas A. Miller a a Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA b Department of Cancer Biology and Therapeutics, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA c Department of Oncology and Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA d Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA Received 21 November 2007; revised 11 December 2007; accepted 13 December 2007 Available online 7 January 2008 Abstract—We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we pos- tulate that the SHI-1:2 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain. Ó 2008 Elsevier Ltd. All rights reserved. The histone deacetylase (HDAC) family of metalloen- zymes is extensively involved in epigenetic regulation of gene expression. 1 They catalyze the cleavage of the N-acetyl group from acetylated lysine residues located on the tails of the core nucleosomal histones H2a, H2b, H3, and H4. However overexpression of histone deacetylase leads to hypoacetylated chromatin that be- comes inaccessible to transcription factors, for example. These enzymes also regulate the acetylation status of numerous nonhistone proteins such as transcription fac- tors p53, STAT1, and NF-jB as well as a-tubulin, Hsp90, and Ku70. 2 There are 11 zinc-dependent HDAC enzymes character- ized to date, divided into three classes. Class I enzymes (HDACs 1–3 and 8) are 350–500 amino acids in length, are ubiquitously expressed, and are located primarily in the nucleus. Class II enzymes (HDACs 4–7, 9 and 10) are about 1000 amino acids in length, are tissue-specific, and can shuttle between the cytoplasm and the nucleus. HDAC11 contains residues common to both classes and also has tissue-specific expression; and is considered the only class IV HDAC. Seven additional NAD-dependent HDACs comprise Class III. Known as SIRT1–7, this silencing information regulator 2 (Sir2) family of deacet- ylases has a unique catalytic mechanism that requires the cofactor nicotinamide adenine dinucleotide and these enzymes respond to changes in cellular redox. 3 Small molecule inhibitors 4 of histone deacetylase have been shown to activate transcription of genes regulating cell-cycle progression, differentiation, and/or apoptosis in cancer cells and these agents generally conform to a broadly accepted pharmacophore. In late 2006, Zolin- za TM became the first HDAC inhibitor to gain FDA ap- proval and is used for the treatment of the cutaneous manifestations of T-cell lymphoma (Fig. 1). 5 Like many 0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2007.12.031 Keywords: HDAC inhibitor; Isoform selectivity; HDAC3; Internal cavity; Biaryl. * Corresponding author. Tel.: +1 617 992 2054; fax: +1 617 992 2403; e-mail: joey_methot@merck.com   Present address: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. Available online at www.sciencedirect.com Bioorganic & Medicinal Chemistry Letters 18 (2008) 973–978