(2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-tert-butyl-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol

ID: ALA3414626

Max Phase: Phase

Molecular Formula: C30H42N8O3

Molecular Weight: 562.72

Molecule Type: Small molecule

Names and Identifiers

Synonyms: Pinometostat | Pinometostat anhydrous | EPZ-005676 | EPZ-5676

Canonical SMILES:  CC(C)N(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O)[C@H]1C[C@@H](CCc2nc3cc(C(C)(C)C)ccc3[nH]2)C1

Standard InChI:  InChI=1S/C30H42N8O3/c1-16(2)37(13-22-25(39)26(40)29(41-22)38-15-34-24-27(31)32-14-33-28(24)38)19-10-17(11-19)6-9-23-35-20-8-7-18(30(3,4)5)12-21(20)36-23/h7-8,12,14-17,19,22,25-26,29,39-40H,6,9-11,13H2,1-5H3,(H,35,36)(H2,31,32,33)/t17-,19+,22-,25-,26-,29-/m1/s1

Standard InChI Key:  LXFOLMYKSYSZQS-LURJZOHASA-N

Molfile:  

     RDKit          2D

 41 46  0  0  1  0  0  0  0  0999 V2000
   -3.4957   -2.5703    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -4.6859   -2.7233    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -5.4132   -1.7688    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -5.2654   -4.1077    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   -4.3533   -5.2996    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.8675   -5.1069    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.1519   -3.7886    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   -0.6928   -4.0817    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.4810   -5.5489    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.5772   -6.1149    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   -1.8348   -6.1949    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.0533   -7.3748    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    0.3114   -2.9665    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    1.8032   -3.1233    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.4133   -1.7530    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    1.2990   -0.7500    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.2990    0.7500    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.3383    1.3500    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    0.0000    1.5000    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   -1.2990    0.7500    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.2990   -0.7500    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    0.0000   -1.5000    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -6.7537   -4.3007    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -7.8926   -3.3810    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -8.8056   -4.5711    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  -10.2880   -4.7633    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  -11.2000   -3.5714    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  -12.6884   -3.7644    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  -13.6993   -2.6736    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
  -15.0523   -3.3193    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  -16.4382   -2.7454    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  -17.6281   -3.6587    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  -17.4322   -5.1458    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  -16.0464   -5.7197    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  -14.8564   -4.8065    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  -13.3823   -5.0798    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
  -19.0148   -3.0844    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  -19.1723   -1.8948    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  -19.9665   -3.8153    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  -20.1237   -2.6258    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -7.6155   -5.4841    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  1  2  1  0
  2  3  1  0
  2  4  1  0
  4  5  1  0
  6  5  1  1
  6  7  1  0
  7  8  1  0
  8  9  1  0
  9 10  1  6
  9 11  1  0
 11  6  1  0
 11 12  1  6
  8 13  1  1
 13 14  1  0
 14 15  2  0
 15 16  1  0
 16 17  2  0
 17 18  1  0
 17 19  1  0
 19 20  2  0
 20 21  1  0
 21 22  2  0
 22 13  1  0
 22 16  1  0
 23  4  1  1
 23 24  1  0
 24 25  1  0
 25 26  1  1
 26 27  1  0
 27 28  1  0
 28 29  2  0
 29 30  1  0
 30 31  2  0
 31 32  1  0
 32 33  2  0
 33 34  1  0
 34 35  2  0
 35 30  1  0
 35 36  1  0
 36 28  1  0
 32 37  1  0
 37 38  1  0
 37 39  1  0
 37 40  1  0
 25 41  1  0
 41 23  1  0
M  END

Alternative Forms

1. Parent:

   

   ALA3414626

   PINOMETOSTAT

Molecule Features

Natural Product: No

Oral: No

Chemical Probe: No

Parenteral: No

Molecule Type: Small molecule

Topical: No

First In Class: No

Black Box: No

Chirality: Yes

Availability: No

Prodrug: No

Calculated Properties

Molecular Weight: 562.72

Molecular Weight (Monoisotopic): 562.3380

AlogP: 3.32

#Rotatable Bonds: 8

Polar Surface Area: 151.23

Molecular Species: BASE

HBA: 10

HBD: 4

#RO5 Violations: 1

HBA (Lipinski): 11

HBD (Lipinski): 5

#RO5 Violations (Lipinski): 2

CX Acidic pKa: 12.28

CX Basic pKa: 9.05

CX LogP: 3.31

CX LogD: 1.61

Aromatic Rings: 4

Heavy Atoms: 41

QED Weighted: 0.25

Np Likeness Score: -0.18

References

1. Kaniskan HÜ, Konze KD, Jin J..  (2015)  Selective inhibitors of protein methyltransferases.,  58  (4): [PMID:25406853] [10.1021/jm501234a]

2.  (2016)  Combination therapy for treating cancer, 

3. Möbitz H, Machauer R, Holzer P, Vaupel A, Stauffer F, Ragot C, Caravatti G, Scheufler C, Fernandez C, Hommel U, Tiedt R, Beyer KS, Chen C, Zhu H, Gaul C..  (2017)  Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach.,  8  (3): [PMID:28337327] [10.1021/acsmedchemlett.6b00519]

4. Liu T, Xie W, Li C, Ren H, Mao Y, Chen G, Cheng M, Zhao D, Shen J, Li J, Zhou Y, Xiong B, Chen YL..  (2017)  Preparation of 5'-deoxy-5'-amino-5'-C-methyl adenosine derivatives and their activity against DOT1L.,  27  (22): [PMID:29050780] [10.1016/j.bmcl.2017.10.019]

5. Unpublished dataset, 

6. Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek.  (2020)  Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection,  [10.21203/rs.3.rs-23951/v1]

7. Egbert M, Whitty A, Keserű GM, Vajda S..  (2019)  Why Some Targets Benefit from beyond Rule of Five Drugs.,  62  (22): [PMID:31188592] [10.1021/acs.jmedchem.8b01732]

8. Stauffer F, Weiss A, Scheufler C, Möbitz H, Ragot C, Beyer KS, Calkins K, Guthy D, Kiffe M, Van Eerdenbrugh B, Tiedt R, Gaul C..  (2019)  New Potent DOT1L Inhibitors for in Vivo Evaluation in Mouse.,  10  (12): [PMID:31857842] [10.1021/acsmedchemlett.9b00452]

9. Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani.  (2020)  Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen,  [10.6019/CHEMBL4495564]

10. Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani.  (2020)  Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen,  [10.6019/CHEMBL4495564]

11. Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen.  (2020)  Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort,  [10.6019/CHEMBL4495565]

12. Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen.  (2020)  Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort,  [10.6019/CHEMBL4495565]

13. Bernhard Ellinger, Justus Dick, Vanessa Lage-Rupprecht, Bruce Schultz, Andrea Zaliani, Marcin Namysl, Stephan Gebel, Ole Pless, Jeanette Reinshagen, Christian Ebeling, Alexander Esser, Marc Jacobs, Carsten Claussen, and Martin Hofmann-Apitius.  (2021)  HDAC6 screening dataset using tau-based substrate in an enzymatic assay yields selective inhibitors and activators,  [10.6019/CHEMBL4808148]

14. Khirsariya P, Pospíšil P, Maier L, Boudný M, Babáš M, Kroutil O, Mráz M, Vácha R, Paruch K..  (2022)  Synthesis and Profiling of Highly Selective Inhibitors of Methyltransferase DOT1L Based on Carbocyclic C-Nucleosides.,  65  (7.0): [PMID:35302777] [10.1021/acs.jmedchem.1c02228]

15. Yuan Y, Du L, Tan R, Yu Y, Jiang J, Yao A, Luo J, Tang R, Xiao Y, Sun H..  (2022)  Design, Synthesis, and Biological Evaluations of DOT1L Peptide Mimetics Targeting the Protein-Protein Interactions between DOT1L and MLL-AF9/MLL-ENL.,  65  (11.0): [PMID:35612819] [10.1021/acs.jmedchem.2c00083]

Source

Source(5):

• Scientific Literature
• Clinical Candidates
• BindingDB Database
• SARS-CoV-2 Screening Data 2020-21
• Fraunhofer HDAC6