Rino Ragno Rome Center for Molecular Design Department of Chemistry and Phamaceutical Technology Faculty of Pharmacy and Medicine

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1 Rino Ragno Rome Center for Molecular Design Department of Chemistry and Phamaceutical Technology Faculty of Pharmacy and Medicine

2 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 2

3 Genetics Mutation FF * * * Gene EpiGenetics DNA methylation Methylated DNA promoter FF Gene Deletion FF Gene Chromatin remodeling HDAC promoter FF Gene Gene Therapy Epigenetic Therapy Epigenetics (1997): the study of meiotically/mitotically heritable changes in gene expression that are not caused by alteration of the DNA sequence HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 3

4 acetylation/ deacetylation phosphorylation methylation/ demethylation ADPribosylation ubiquitination DNA methylation Histone Code HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 4

5 Apoptosis Pathways death receptor ptw TNF family ligands and receptors (ie, TRAIL, Fas) mitochondrial death ptw Bim, Bmf, APAF1, caspase 9 BCL2, BCL-X L, MCL1, XIAP RS production indirect gene expression regulation Ac E2F1, p53, STAT1, STAT3, NF-κB transcription-independent effects Ac Ku70 HDAC6-PP1-α-tubulin complex Ac α-tubulin Ac HSP90 degradation of client proteins HDACi Anti-Angiogenic Effects VEGF bfgf HIF1α TIE2 ens CXCR4 angiopoietin Immunomodulatory Effects MHCs, MICA, MICB CD40, CD80, CD86 ICAM1 TNFα IL1 IFNγ Bolden, J.E. et al., Nat. Rev. Drug Discov. 2006, 5, HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 5

6 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 6

7 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 7

8 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 8

9 class compd [range] Short-Chain Fatty Acids Sodium Butyrate mm HDAC specificity class I, IIa clinical trials Phase I, II (colorectal) Valproic Acid mm class I, IIa Phase I, II (AML, leukemias) AN-9 μm NA Phase I, II HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 9

10 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 10

11 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 11

12 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 12

13 His 132 NH N NH - H Zn H Asp 173 N NH - His 131 Tyr 297 Asp 166 Finnin, M.S. et al., Nature 1999, 401, HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 13

14 H X (CH 2 ) n R X (CH 2 ) n N H N S NH HN N H H N H CH 3 H N H SH S CH 3 ( ) n CAP X HS ZBG R N HN NH HN N (un)saturated C 4-6 chain With/out ring Insertion CH 3 H R 1 R S N S HN N HN H 2 N CH 2 H HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 14

15 Res1 Res2 Res3 Res-n SAHA Cplx 1 Cplx 2 Cplx 3 Cplx m X1 X2 X3 Xn X1 X2 X3 Xn X1 X2 X3 Xn X1 X2 X3 Xn PLS Y1 Y2 Y3 Ym CMBINE Model HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 15

16 Proteins: Structure, Function, and Bioinformatics, 2010, 78, HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 16

17 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 17

18 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 18

19 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 19

20 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 20

21 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 21

22 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 22

23 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 23

24 Redocking results (RMSD) with AutoDockVina Complex name Best docked Best Cluster Best Fit LLX.HDAC HA3.HDAC TMFK.HDAC SAHA.HDAC TSA.HDAC APHA.HDAC SAHA.HDAC TSA.HDAC DA % HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 24

25 CPH M4T HN H N ModWeb CH 3 APHA8 in HDAC1 SwissModel HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 25

26 HN H N CH 3 APHA8 in HDAC1 CPH ModWeb M4T SwissModel HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 26

27 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 27

28 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 28

29 H 3 C N H 3 C H 3 C H 3 C N H H HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 29

30 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 30

31 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 31

32 DRY ELE Decreasing Activity Increasing Activity Decreasing Activity Increasing Activity HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 32

33 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 33

34 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 34

35 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 35

36 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 36

37 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 37

38 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 38

39 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 39

40 S N HN S N N H SH HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 40

41 N N H H N H 2 N ELE DRY HDAC3 HDAC4 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 41

42 N H N H HDAC6-1 HDAC8 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 42

43 HDAC Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction 43