(R,Z)-5-(2,6-dichlorobenzylsulfonyl)-3-((3,5-dimethyl-4-(2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carbonyl)-1H-pyrrol-2-yl)methylene)indolin-2-one

ID: ALA450786

Cas Number: 477575-56-7

PubChem CID: 10461815

Product Number: P125191, Order Now?

Max Phase: Preclinical

Molecular Formula: C32H34Cl2N4O4S

Molecular Weight: 641.62

Molecule Type: Small molecule

Names and Identifiers

Synonyms: TCMDC-125885 | PHA-665752 | TCMDC-125885 | PHA-665752|477575-56-7|PHA 665752|PHA665752|PHA-665752 hydrate|TCMDC-125885|UNII-0VXU5T5R3J|(2R)-1-[[5-[(Z)-[5-[[(2,6-DICHLOROPHENYL)METHYL]SULFONYL]-1,2-DIHYDRO-2-OXO-3H-INDOL-3-YLIDENE]METHYL]-2,4-DIMETHYL-1H-PYRROL-3-YL]CARBONYL]-2-(1-PYRROLIDINYLMETHYL)PYRROLIDINE|0VXU5T5R3J|(R,Z)-5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-(2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carbonyl)-1H-pyrrol-2-yl)methylene)indolin-2-one|CHEMBL450786|CHEBI:90197|(R,Z)Show More⌵

Canonical SMILES:  Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@@H]1CN1CCCC1

Standard InChI:  InChI=1S/C32H34Cl2N4O4S/c1-19-29(35-20(2)30(19)32(40)38-14-6-7-21(38)17-37-12-3-4-13-37)16-24-23-15-22(10-11-28(23)36-31(24)39)43(41,42)18-25-26(33)8-5-9-27(25)34/h5,8-11,15-16,21,35H,3-4,6-7,12-14,17-18H2,1-2H3,(H,36,39)/b24-16-/t21-/m1/s1

Standard InChI Key:  OYONTEXKYJZFHA-SSHUPFPWSA-N

Molfile:  

     RDKit          2D

 43 48  0  0  0  0  0  0  0  0999 V2000
   10.7997    0.5931    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   11.5162    1.0065    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   11.5133    1.8370    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   10.7979    2.2461    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   10.0849    1.0060    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   10.0862    1.8349    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.2982    2.0923    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    8.8099    1.4224    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.2962    0.7511    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.9849    1.4236    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    9.0401   -0.0331    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    8.2532   -0.2796    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.5882    0.2095    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    6.9157   -0.2685    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.1627   -1.0558    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.9874   -1.0643    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    6.1338   -0.0054    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    8.4647   -1.7372    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    6.7479   -1.7689    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.9229   -1.7663    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    7.1581   -2.4847    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    5.4381   -1.1016    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.6527   -1.3540    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.6500   -2.1791    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.4338   -2.4364    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.6868   -3.2217    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.1331   -3.8333    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    4.3168   -3.7500    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.9793   -4.5028    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.5910   -5.0564    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.3064   -4.6457    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   12.2313    0.5951    0.0000 S   0  0  0  0  0  0  0  0  0  0  0  0
   12.9451    1.0087    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   13.6602    0.5973    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   13.6568   -0.2261    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   14.3711   -0.6374    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.0859   -0.2237    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.0820    0.6056    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   14.3671    1.0131    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   14.3616    1.8381    0.0000 Cl  0  0  0  0  0  0  0  0  0  0  0  0
   12.9418   -0.6375    0.0000 Cl  0  0  0  0  0  0  0  0  0  0  0  0
   11.6417    0.0125    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   12.8125    0.0125    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
  4  6  1  0
 19 21  2  0
 20 22  1  0
  8 10  2  0
  5  6  2  0
  9 11  2  0
  1  2  2  0
 22 23  1  0
 23 24  1  0
 24 25  1  0
 25 20  1  0
 11 12  1  0
 25 26  1  1
 12 13  1  0
 26 27  1  0
 27 28  1  0
  5  1  1  0
  2  3  1  0
  3  4  2  0
 28 29  1  0
 29 30  1  0
 30 31  1  0
 31 27  1  0
 13 14  1  0
  2 32  1  0
 14 15  2  0
 32 33  1  0
 15 16  1  0
 33 34  1  0
 16 12  2  0
 34 35  2  0
  6  7  1  0
 35 36  1  0
 14 17  1  0
 36 37  2  0
  7  8  1  0
 37 38  1  0
 16 18  1  0
 38 39  2  0
 39 34  1  0
  8  9  1  0
 39 40  1  0
 15 19  1  0
 35 41  1  0
  9  5  1  0
 32 42  2  0
 19 20  1  0
 32 43  2  0
M  END

Alternative Forms

1. Parent:

   

   ALA450786

   PHA-665752

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: No

Availability: No

Prodrug: No

Calculated Properties

Molecular Weight: 641.62

Molecular Weight (Monoisotopic): 640.1678

AlogP: 6.11

#Rotatable Bonds: 7

Polar Surface Area: 102.58

Molecular Species: BASE

HBA: 5

HBD: 2

#RO5 Violations: 2

HBA (Lipinski): 8

HBD (Lipinski): 2

#RO5 Violations (Lipinski): 2

CX Acidic pKa: 10.73

CX Basic pKa: 8.97

CX LogP: 4.98

CX LogD: 3.51

Aromatic Rings: 3

Heavy Atoms: 43

QED Weighted: 0.30

Np Likeness Score: -1.20

References

1. McDermott U, Sharma SV, Dowell L, Greninger P, Montagut C, Lamb J, Archibald H, Raudales R, Tam A, Lee D, Rothenberg SM, Supko JG, Sordella R, Ulkus LE, Iafrate AJ, Maheswaran S, Njauw CN, Tsao H, Drew L, Hanke JH, Ma XJ, Erlander MG, Gray NS, Haber DA, Settleman J..  (2007)  Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling.,  104  (50): [PMID:18077425] [10.1073/pnas.0707498104]

2. Raeppel S, Claridge S, Saavedra O, Gaudette F, Zhan L, Mannion M, Zhou N, Raeppel F, Granger MC, Isakovic L, Déziel R, Nguyen H, Beaulieu N, Beaulieu C, Dupont I, Robert MF, Lefebvre S, Dubay M, Rahil J, Wang J, Ste-Croix H, Robert Macleod A, Besterman J, Vaisburg A..  (2009)  N-(3-fluoro-4-(2-arylthieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides: a novel series of dual c-Met/VEGFR2 receptor tyrosine kinase inhibitors.,  19  (5): [PMID:19211249] [10.1016/j.bmcl.2009.01.068]

3. Gamo FJ, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera JL, Vanderwall DE, Green DV, Kumar V, Hasan S, Brown JR, Peishoff CE, Cardon LR, Garcia-Bustos JF..  (2010)  Thousands of chemical starting points for antimalarial lead identification.,  465  (7296): [PMID:20485427] [10.1038/nature09107]

4. Mannion M, Raeppel S, Claridge S, Zhou N, Saavedra O, Isakovic L, Zhan L, Gaudette F, Raeppel F, Déziel R, Beaulieu N, Nguyen H, Chute I, Beaulieu C, Dupont I, Robert MF, Lefebvre S, Dubay M, Rahil J, Wang J, Ste-Croix H, Robert Macleod A, Besterman JM, Vaisburg A..  (2009)  N-(4-(6,7-Disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides: a novel series of dual c-Met/VEGFR2 receptor tyrosine kinase inhibitors.,  19  (23): [PMID:19854051] [10.1016/j.bmcl.2009.10.040]

5. Cui JJ, Tran-Dubé M, Shen H, Nambu M, Kung PP, Pairish M, Jia L, Meng J, Funk L, Botrous I, McTigue M, Grodsky N, Ryan K, Padrique E, Alton G, Timofeevski S, Yamazaki S, Li Q, Zou H, Christensen J, Mroczkowski B, Bender S, Kania RS, Edwards MP..  (2011)  Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK).,  54  (18): [PMID:21812414] [10.1021/jm2007613]

6. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP..  (2011)  Comprehensive analysis of kinase inhibitor selectivity.,  29  (11): [PMID:22037378] [10.1038/nbt.1990]

7. Jester BW, Gaj A, Shomin CD, Cox KJ, Ghosh I..  (2012)  Testing the promiscuity of commercial kinase inhibitors against the AGC kinase group using a split-luciferase screen.,  55  (4): [PMID:22257127] [10.1021/jm201265f]

8. Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute,  [10.6019/CHEMBL1201861]

9. St. Jude Leishmania screening dataset.,  [10.6019/CHEMBL3433997]

10. PubChem BioAssay data set, 

11. Zhang J, Jiang X, Jiang Y, Guo M, Zhang S, Li J, He J, Liu J, Wang J, Ouyang L..  (2016)  Recent advances in the development of dual VEGFR and c-Met small molecule inhibitors as anticancer drugs.,  108  [PMID:26717201] [10.1016/j.ejmech.2015.12.016]

12. 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]

13. Yang T, Ng WH, Chen H, Chomchopbun K, Huynh TH, Go ML, Kon OL..  (2016)  Mitochondrial-Targeting MET Kinase Inhibitor Kills Erlotinib-Resistant Lung Cancer Cells.,  7  (8): [PMID:27563407] [10.1021/acsmedchemlett.6b00223]

14. 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]

15. 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]

16. Němec V,Maier L,Berger BT,Chaikuad A,Drápela S,Souček K,Knapp S,Paruch K.  (2021)  Highly selective inhibitors of protein kinases CLK and HIPK with the furo[3,2-b]pyridine core.,  215  [PMID:33636538] [10.1016/j.ejmech.2021.113299]

17.  (2020)  Compositions and methods for treating beta-globinopathies, 

18. 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]

19. Gilda Padalino, Avril Coghlan, Giampaolo Pagliuca, Josephine F. Thomas, Matthew Berriman, Karl F. Hoffmann.  (2023)  Using ChEMBL to complement schistosome drug discovery,  [10.6019/CHEMBL5096127]

Source

Source(9):

• Scientific Literature
• GSK Malaria Screening
• Sanger Institute Genomics of Drug Sensitivity in Cancer
• PubChem BioAssays
• St Jude Leishmania Screening
• Patent Bioactivity Data
• SARS-CoV-2 Screening Data 2020-21
• Fraunhofer HDAC6
• Cardiff Schistosomiasis Dataset 2023