ID: ALA289228

Max Phase: Phase

Molecular Formula: C27H22Cl2N4O

Molecular Weight: 489.41

Molecule Type: Small molecule

Representations

Synonyms (6): Tipifarnib | Zarnestra | NSC-702818 | R-11577 | R-115777 | R115777
Synonyms from Alternative Forms(6):

Canonical SMILES:  Cn1cncc1[C@@](N)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C

Standard InChI:  InChI=1S/C27H22Cl2N4O/c1-32-16-31-15-25(32)27(30,18-6-9-20(28)10-7-18)19-8-11-24-23(13-19)22(14-26(34)33(24)2)17-4-3-5-21(29)12-17/h3-16H,30H2,1-2H3/t27-/m1/s1

Standard InChI Key:  PLHJCIYEEKOWNM-HHHXNRCGSA-N

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

Properties

Molecular Weight: 489.41

Molecular Weight (Monoisotopic): 488.1171

AlogP: 5.50

#Rotatable Bonds: 4

Polar Surface Area: 65.84

Molecular Species: NEUTRAL

HBA: 5

HBD: 1

#RO5 Violations: 1

HBA (Lipinski): 5

HBD (Lipinski): 2

#RO5 Violations (Lipinski): 1

CX Acidic pKa:

CX Basic pKa: 7.50

CX LogP: 4.69

CX LogD: 4.34

Aromatic Rings: 5

Heavy Atoms: 34

QED Weighted: 0.36

Np Likeness Score: -0.73

References

1. Curtin ML, Florjancic AS, Cohen J, Gu WZ, Frost DJ, Muchmore SW, Sham HL..  (2003)  Novel and selective imidazole-containing biphenyl inhibitors of protein farnesyltransferase.,  13  (7): [PMID:12657284] [10.1016/s0960-894x(03)00096-9]

2. Angibaud P, Bourdrez X, Devine A, End DW, Freyne E, Ligny Y, Muller P, Mannens G, Pilatte I, Poncelet V, Skrzat S, Smets G, Van Dun J, Van Remoortere P, Venet M, Wouters W..  (2003)  5-imidazolyl-quinolinones, -quinazolinones and -benzo-azepinones as farnesyltransferase inhibitors.,  13  (9): [PMID:12699751] [10.1016/s0960-894x(03)00180-x]

3. Bell IM..  (2004)  Inhibitors of farnesyltransferase: a rational approach to cancer chemotherapy?,  47  (8): [PMID:15055985] [10.1021/jm0305467]

4. Angibaud P, Saha AK, Bourdrez X, End DW, Freyne E, Lezouret P, Mannens G, Mevellec L, Meyer C, Pilatte I, Poncelet V, Roux B, Smets G, Van Dun J, Venet M, Wouters W..  (2003)  4-methyl-1,2,4-triazol-3-yl heterocycle as an alternative to the 1-methylimidazol-5-yl moiety in the farnesyltransferase inhibitor ZARNESTRA.,  13  (24): [PMID:14643326] [10.1016/j.bmcl.2003.09.043]

5. Angibaud P, Bourdrez X, End DW, Freyne E, Janicot M, Lezouret P, Ligny Y, Mannens G, Damsch S, Mevellec L, Meyer C, Muller P, Pilatte I, Poncelet V, Roux B, Smets G, Van Dun J, Van Remoortere P, Venet M, Wouters W..  (2003)  Substituted azoloquinolines and -quinazolines as new potent farnesyl protein transferase inhibitors.,  13  (24): [PMID:14643327] [10.1016/j.bmcl.2003.08.080]

6. Wang L, Wang GT, Wang X, Tong Y, Sullivan G, Park D, Leonard NM, Li Q, Cohen J, Gu WZ, Zhang H, Bauch JL, Jakob CG, Hutchins CW, Stoll VS, Marsh K, Rosenberg SH, Sham HL, Lin NH..  (2004)  Design, synthesis, and biological activity of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles as potent and selective farnesyltransferase inhibitors.,  47  (3): [PMID:14736242] [10.1021/jm030434f]

7. Li Q, Claiborne A, Li T, Hasvold L, Stoll VS, Muchmore S, Jakob CG, Gu W, Cohen J, Hutchins C, Frost D, Rosenberg SH, Sham HL..  (2004)  Design, synthesis, and activity of 4-quinolone and pyridone compounds as nonthiol-containing farnesyltransferase inhibitors.,  14  (21): [PMID:15454228] [10.1016/j.bmcl.2004.08.012]

8. Li Q, Wang GT, Li T, Gwaltney SL, Woods KW, Claiborne A, Wang X, Gu W, Cohen J, Stoll VS, Hutchins C, Frost D, Rosenberg SH, Sham HL..  (2004)  Synthesis and activity of 1-aryl-1'-imidazolyl methyl ethers as non-thiol farnesyltransferase inhibitors.,  14  (21): [PMID:15454229] [10.1016/j.bmcl.2004.08.011]

9. Hucke O, Gelb MH, Verlinde CL, Buckner FS..  (2005)  The protein farnesyltransferase inhibitor Tipifarnib as a new lead for the development of drugs against Chagas disease.,  48  (17): [PMID:16107140] [10.1021/jm050441z]

10. Nallan L, Bauer KD, Bendale P, Rivas K, Yokoyama K, Hornéy CP, Pendyala PR, Floyd D, Lombardo LJ, Williams DK, Hamilton A, Sebti S, Windsor WT, Weber PC, Buckner FS, Chakrabarti D, Gelb MH, Van Voorhis WC..  (2005)  Protein farnesyltransferase inhibitors exhibit potent antimalarial activity.,  48  (11): [PMID:15916422] [10.1021/jm0491039]

11. Li Q, Woods KW, Wang W, Lin NH, Claiborne A, Gu WZ, Cohen J, Stoll VS, Hutchins C, Frost D, Rosenberg SH, Sham HL..  (2005)  Design, synthesis, and activity of achiral analogs of 2-quinolones and indoles as non-thiol farnesyltransferase inhibitors.,  15  (8): [PMID:15808463] [10.1016/j.bmcl.2005.02.062]

12. Li Q, Li T, Woods KW, Gu WZ, Cohen J, Stoll VS, Galicia T, Hutchins C, Frost D, Rosenberg SH, Sham HL..  (2005)  Benzimidazolones and indoles as non-thiol farnesyltransferase inhibitors based on tipifarnib scaffold: synthesis and activity.,  15  (11): [PMID:15911281] [10.1016/j.bmcl.2005.03.049]

13. Kraus JM, Verlinde CL, Karimi M, Lepesheva GI, Gelb MH, Buckner FS..  (2009)  Rational modification of a candidate cancer drug for use against Chagas disease.,  52  (6): [PMID:19239254] [10.1021/jm801313t]

14. Chennamaneni NK, Arif J, Buckner FS, Gelb MH..  (2009)  Isoquinoline-based analogs of the cancer drug clinical candidate tipifarnib as anti-Trypanosoma cruzi agents.,  19  (23): [PMID:19875282] [10.1016/j.bmcl.2009.10.029]

15. Kraus JM, Tatipaka HB, McGuffin SA, Chennamaneni NK, Karimi M, Arif J, Verlinde CL, Buckner FS, Gelb MH..  (2010)  Second generation analogues of the cancer drug clinical candidate tipifarnib for anti-Chagas disease drug discovery.,  53  (10): [PMID:20429511] [10.1021/jm9013136]

16. Gelb MH, Brunsveld L, Hrycyna CA, Michaelis S, Tamanoi F, Van Voorhis WC, Waldmann H..  (2006)  Therapeutic intervention based on protein prenylation and associated modifications.,  2  (10): [PMID:16983387] [10.1038/nchembio818]

17. Vizirianakis IS, Chatzopoulou M, Bonovolias ID, Nicolaou I, Demopoulos VJ, Tsiftsoglou AS..  (2010)  Toward the development of innovative bifunctional agents to induce differentiation and to promote apoptosis in leukemia: clinical candidates and perspectives.,  53  (19): [PMID:20925433] [10.1021/jm100189a]

18. Kim HJ, Lee SH, Koh JS, Lee SH..  (2012)  Preclinical metabolism of LB42908, a novel farnesyl transferase inhibitor, and its effects on the cytochrome P450 isozyme activities.,  22  (9): [PMID:22497764] [10.1016/j.bmcl.2012.03.070]

19. USP Dictionary of USAN and International Names (2010 edition) and USAN registrations 2007-date, 

20. PubChem BioAssay data set, 

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

22. Yu X, Zhao X, Zhu L, Zou C, Liu X, Zhao Z, Huang J, Li H.  (2013)  Discovery of novel inhibitors for human farnesyltransferase (hFTase) via structure-based virtual screening,  4  (6): [10.1039/C3MD00058C]

23. Ochocki JD, Distefano MD..  (2013)  Prenyltransferase Inhibitors: Treating Human Ailments from Cancer to Parasitic Infections.,  4  (3): [PMID:25530833] [10.1039/c2md20299a]

24. Mark Wenlock and Nicholas Tomkinson. Experimental in vitro DMPK and physicochemical data on a set of publicly disclosed compounds,  [10.6019/CHEMBL3301361]

25. Unpublished dataset, 

26. Buuh ZY, Lyu Z, Wang RE..  (2018)  Interrogating the Roles of Post-Translational Modifications of Non-Histone Proteins.,  61  (8): [PMID:28505447] [10.1021/acs.jmedchem.6b01817]

27. 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]

28. 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]

29. 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]

30. 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]

31. 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]

32. Johannes Zuegg, Alysha Elliott, Maite Amado, Emma Cowie, Ali Hinton, Geraldine Kaeslin, Angela Kavanagh, Anne Kunert, Gabriell Lowe, Soumya Ramu, Janet Reid, Robin Trauer, Mathilde Desselle, Ruth Neale, Karl Hansford, Mark Blascovich, Matthew Cooper. CO-ADD screening of MMV (CH) - Pandemic Response Box,  [10.6019/CHEMBL4513161]

33. Homerin G, Nica AS, Farce A, Dubois J, Ghinet A..  (2020)  Ultrasounds-mediated 10-seconds synthesis of chalcones as potential farnesyltransferase inhibitors.,  30  (11): [PMID:32247731] [10.1016/j.bmcl.2020.127149]

34. Ellen Van Damme.  (2021)  Screening of ~5500 FDA-approved drugs and clinical candidates for anti-SARS-CoV-2 activity,  [10.6019/CHEMBL4651402]

35. 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]

36. Korzeniecki C, Priefer R..  (2021)  Targeting KRAS mutant cancers by preventing signaling transduction in the MAPK pathway.,  211  [PMID:33228976] [10.1016/j.ejmech.2020.113006]

Source

Source(10):

• Scientific Literature
• Sanger Institute Genomics of Drug Sensitivity in Cancer
• PubChem BioAssays
• Clinical Candidates
• USP Dictionary of USAN and International Drug Names
• AstraZeneca Deposited Data
• CO-ADD antimicrobial screening data
• SARS-CoV-2 Screening Data 2020-21
• IMI-CARE SARS-CoV-2 Data
• Fraunhofer HDAC6