ID: ALA608533

Max Phase: Approved

First Approval: 2017

Molecular Formula: C35H30N4O4

Molecular Weight: 570.65

Molecule Type: Small molecule

Representations

Synonyms (8): Midostaurin | Pkc-412 | CGP 41251 | CGP-41251 | NSC-656576 | NVP-PKC412 | PKC 412 | PKC-412
Synonyms from Alternative Forms(8):

Trade Names(1): Rydapt

Canonical SMILES:  CO[C@@H]1[C@H](N(C)C(=O)c2ccccc2)C[C@H]2O[C@]1(C)n1c3ccccc3c3c4c(c5c6ccccc6n2c5c31)C(=O)NC4

Standard InChI:  InChI=1S/C35H30N4O4/c1-35-32(42-3)25(37(2)34(41)19-11-5-4-6-12-19)17-26(43-35)38-23-15-9-7-13-20(23)28-29-22(18-36-33(29)40)27-21-14-8-10-16-24(21)39(35)31(27)30(28)38/h4-16,25-26,32H,17-18H2,1-3H3,(H,36,40)/t25-,26-,32-,35+/m1/s1

Standard InChI Key:  BMGQWWVMWDBQGC-IIFHNQTCSA-N

Molecule Features

Natural Product: No

Oral: Yes

Chemical Probe: No

Parenteral: No

Molecule Type: Small molecule

Topical: No

First In Class: Yes

Black Box: No

Chirality: Yes

Availability: Yes

Prodrug: No

Properties

Molecular Weight: 570.65

Molecular Weight (Monoisotopic): 570.2267

AlogP: 5.91

#Rotatable Bonds: 3

Polar Surface Area: 77.73

Molecular Species: NEUTRAL

HBA: 6

HBD: 1

#RO5 Violations: 2

HBA (Lipinski): 8

HBD (Lipinski): 1

#RO5 Violations (Lipinski): 2

CX Acidic pKa: 13.51

CX Basic pKa:

CX LogP: 5.43

CX LogD: 5.43

Aromatic Rings: 6

Heavy Atoms: 43

QED Weighted: 0.29

Np Likeness Score: 0.66

References

1. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP..  (2008)  A quantitative analysis of kinase inhibitor selectivity.,  26  (1): [PMID:18183025] [10.1038/nbt1358]

2. Mashkani B, Griffith R, Ashman LK..  (2010)  Colony stimulating factor-1 receptor as a target for small molecule inhibitors.,  18  (5): [PMID:20156689] [10.1016/j.bmc.2010.01.056]

3. Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, Karaman MW, Pratz KW, Pallares G, Chao Q, Sprankle KG, Patel HK, Levis M, Armstrong RC, James J, Bhagwat SS..  (2009)  AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML).,  114  (14): [PMID:19654408] [10.1182/blood-2009-05-222034]

4. Shallal HM, Russu WA..  (2011)  Discovery, synthesis, and investigation of the antitumor activity of novel piperazinylpyrimidine derivatives.,  46  (6): [PMID:21429632] [10.1016/j.ejmech.2011.02.057]

5. Guagnano V, Furet P, Spanka C, Bordas V, Le Douget M, Stamm C, Brueggen J, Jensen MR, Schnell C, Schmid H, Wartmann M, Berghausen J, Drueckes P, Zimmerlin A, Bussiere D, Murray J, Graus Porta D..  (2011)  Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase.,  54  (20): [PMID:21936542] [10.1021/jm2006222]

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. Heidary DK, Huang G, Boucher D, Ma J, Forster C, Grey R, Xu J, Arnost M, Choquette D, Chen G, Zhou JH, Yao YM, Ball ED, Namchuk M, Davies RJ, Henkel G..  (2012)  VX-322: a novel dual receptor tyrosine kinase inhibitor for the treatment of acute myelogenous leukemia.,  55  (2): [PMID:22221201] [10.1021/jm201198w]

8. 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]

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

10. PubChem BioAssay data set, 

11. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ..  (2013)  A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery.,  451  (2): [PMID:23398362] [10.1042/bj20121418]

12. Rohe A, Göllner C, Wichapong K, Erdmann F, Al-Mazaideh GM, Sippl W, Schmidt M..  (2013)  Evaluation of potential Myt1 kinase inhibitors by TR-FRET based binding assay.,  61  [PMID:22770610] [10.1016/j.ejmech.2012.06.007]

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

14. Goodfellow VS, Loweth CJ, Ravula SB, Wiemann T, Nguyen T, Xu Y, Todd DE, Sheppard D, Pollack S, Polesskaya O, Marker DF, Dewhurst S, Gelbard HA..  (2013)  Discovery, synthesis, and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3.,  56  (20): [PMID:24044867] [10.1021/jm401094t]

15. Unpublished dataset, 

16. Chen CT, Hsu JT, Lin WH, Lu CT, Yen SC, Hsu T, Huang YL, Song JS, Chen CH, Chou LH, Yen KJ, Chen CP, Kuo PC, Huang CL, Liu HE, Chao YS, Yeh TK, Jiaang WT..  (2015)  Identification of a potent 5-phenyl-thiazol-2-ylamine-based inhibitor of FLT3 with activity against drug resistance-conferring point mutations.,  100  [PMID:26081023] [10.1016/j.ejmech.2015.05.008]

17. Hatcher JM, Weisberg E, Sim T, Stone RM, Liu S, Griffin JD, Gray NS..  (2016)  Discovery of a Highly Potent and Selective Indenoindolone Type 1 Pan-FLT3 Inhibitor.,  7  (5): [PMID:27190596] [10.1021/acsmedchemlett.5b00498]

18. WHO Anatomical Therapeutic Chemical Classification, 

19. Doris A.Schuetz, Wilhelmus Egbertus Arnout de Witte, Yin Cheong Wong, Bernhard Knasmueller, Lars Richter, Daria B. Kokh, S. Kashif Sadiq, Reggie Bosma, Indira Nederpelt, Laura H. Heitman, Elena Segala, Marta Amaral, Dong Guo, Dorothee Andres, Victoria Georgi, Leigh A. Stoddart, Steve Hill, Robert M. Cooke, Chris De Graaf, Rob Leurs, Matthias Frech, Rebecca C. Wade, Elizabeth Cunera Mariade Lange, Adriaan P. IJzerman, Anke Müller-Fahrnow, Gerhard F. Ecker. K4DD drug target binding kinetics data,  [10.6019/CHEMBL3885741]

20. Unpublished dataset, 

21. Klaeger S, Heinzlmeir S and Wilhelm M et al.  (2017)  The target landscape of clinical kinase drugs.,  358  (6367): [PMID:29191878] [10.1126/science.aan4368]

22. Ren Y, Gallucci JC, Li X, Chen L, Yu J, Kinghorn AD..  (2018)  Crystal Structures and Human Leukemia Cell Apoptosis Inducible Activities of Parthenolide Analogues Isolated from Piptocoma rufescens.,  81  (3): [PMID:29350920] [10.1021/acs.jnatprod.7b01079]

23. British National Formulary (72nd edition), 

24. 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]

25. Katie Heiser, Peter F. McLean, Chadwick T. Davis, Ben Fogelson, Hannah B. Gordon, Pamela Jacobson, Brett Hurst, Ben Miller, Ronald W. Alfa, Berton A. Earnshaw, Mason L. Victors, Yolanda T. Chong, Imran S. Haque, Adeline S. Low, Christopher C. Gibson.  (2020)  Identification of potential treatments for COVID-19 through artificial intelligence-enabled phenomic analysis of human cells infected with SARS-CoV-2,  [10.1101/2020.04.21.054387]

26. David E Gordon, Gwendolyn M Jang, Mehdi Bouhaddou, Jiewei Xu, Kirsten Obernier, Kris M White, Matthew J O'Meara, Veronica V Rezelj, Jeffrey Z Guo, Danielle L Swaney, et al.  (2020)  A SARS-CoV-2 protein interaction map reveals targets for drug repurposing,  [PMID:32353859] [10.1038/s41586-020-2286-9]

27. Baska F, Sipos A, Őrfi Z, Nemes Z, Dobos J, Szántai-Kis C, Szabó E, Szénási G, Dézsi L, Hamar P, Cserepes MT, Tóvári J, Garamvölgyi R, Krekó M, Őrfi L..  (2019)  Discovery and development of extreme selective inhibitors of the ITD and D835Y mutant FLT3 kinases.,  184  [PMID:31614258] [10.1016/j.ejmech.2019.111710]

28. Flick AC, Leverett CA, Ding HX, McInturff E, Fink SJ, Helal CJ, O'Donnell CJ..  (2019)  Synthetic Approaches to the New Drugs Approved During 2017.,  62  (16): [PMID:30939001] [10.1021/acs.jmedchem.9b00196]

29. Yuan T, Qi B, Jiang Z, Dong W, Zhong L, Bai L, Tong R, Yu J, Shi J..  (2019)  Dual FLT3 inhibitors: Against the drug resistance of acute myeloid leukemia in recent decade.,  178  [PMID:31207462] [10.1016/j.ejmech.2019.06.002]

30. Li M, Xu Y, Zuo M, Liu W, Wang L, Zhu W..  (2019)  Semisynthetic Derivatives of Fradcarbazole A and Their Cytotoxicity against Acute Myeloid Leukemia Cell Lines.,  82  (8): [PMID:31361136] [10.1021/acs.jnatprod.9b00468]

31. Lin WH, Wu SY, Yeh TK, Chen CT, Song JS, Shiao HY, Kuo CC, Hsu T, Lu CT, Wang PC, Wu TS, Peng YH, Lin HY, Chen CP, Weng YL, Kung FC, Wu MH, Su YC, Huang KW, Chou LH, Hsueh CC, Yen KJ, Kuo PC, Huang CL, Chen LT, Shih C, Tsai HJ, Jiaang WT..  (2019)  Identification of a Multitargeted Tyrosine Kinase Inhibitor for the Treatment of Gastrointestinal Stromal Tumors and Acute Myeloid Leukemia.,  62  (24): [PMID:31721578] [10.1021/acs.jmedchem.9b01229]

32. Bensinger D, Stubba D, Cremer A, Kohl V, Waßmer T, Stuckert J, Engemann V, Stegmaier K, Schmitz K, Schmidt B..  (2019)  Virtual Screening Identifies Irreversible FMS-like Tyrosine Kinase 3 Inhibitors with Activity toward Resistance-Conferring Mutations.,  62  (5): [PMID:30742435] [10.1021/acs.jmedchem.8b01714]

33. 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]

34. 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]

35. 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]

36. 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]

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

38. Brewitz L,Tumber A,Zhang X,Schofield CJ.  (2020)  Small-molecule active pharmaceutical ingredients of approved cancer therapeutics inhibit human aspartate/asparagine-β-hydroxylase.,  28  (20.0): [PMID:33069066] [10.1016/j.bmc.2020.115675]

39. Shanu-Wilson J,Evans L,Wrigley S,Steele J,Atherton J,Boer J.  (2020)  Biotransformation: Impact and Application of Metabolism in Drug Discovery.,  11  (11): [PMID:33214818] [10.1021/acsmedchemlett.0c00202]

40.  (2020)  Compositions and methods for treating beta-globinopathies, 

41. Jeong P,Moon Y,Lee JH,Lee SD,Park J,Lee J,Kim J,Lee HJ,Kim NY,Choi J,Heo JD,Shin JE,Park HW,Kim YG,Han SY,Kim YC.  (2020)  Discovery of orally active indirubin-3'-oxime derivatives as potent type 1 FLT3 inhibitors for acute myeloid leukemia.,  195  [PMID:32272419] [10.1016/j.ejmech.2020.112205]

42. 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]

43. Wang J, Pan X, Song Y, Liu J, Ma F, Wang P, Liu Y, Zhao L, Kang D, Hu L..  (2021)  Discovery of a Potent and Selective FLT3 Inhibitor (Z)-N-(5-((5-Fluoro-2-oxoindolin-3-ylidene)methyl)-4-methyl-1H-pyrrol-3-yl)-3-(pyrrolidin-1-yl)propanamide with Improved Drug-like Properties and Superior Efficacy in FLT3-ITD-Positive Acute Myeloid Leukemia.,  64  (8.0): [PMID:33797247] [10.1021/acs.jmedchem.0c02247]

44. Tian T, Zhang S, Luo B, Yin F, Lu W, Li Y, Huang K, Liu Q, Huang P, Garcia-Manero G, Wen S, Hu Y..  (2022)  Identification of the Benzoimidazole Compound as a Selective FLT3 Inhibitor by Cell-Based High-Throughput Screening of a Diversity Library.,  65  (4.0): [PMID:35148084] [10.1021/acs.jmedchem.1c02079]

45. Raghuvanshi R, Bharate SB..  (2022)  Recent Developments in the Use of Kinase Inhibitors for Management of Viral Infections.,  65  (2.0): [PMID:33539089] [10.1021/acs.jmedchem.0c01467]

46. Dokla EME, Abdel-Aziz AK, Milik SN, McPhillie MJ, Minucci S, Abouzid KAM..  (2022)  Discovery of a benzimidazole-based dual FLT3/TrKA inhibitor targeting acute myeloid leukemia.,  56  [PMID:35033885] [10.1016/j.bmc.2021.116596]

47. Acharya B, Saha D, Armstrong D, Lakkaniga NR, Frett B..  (2022)  FLT3 inhibitors for acute myeloid leukemia: successes, defeats, and emerging paradigms.,  13  (7.0): [PMID:35923716] [10.1039/d2md00067a]

48. Zhong Y, Qiu RZ, Sun SL, Zhao C, Fan TY, Chen M, Li NG, Shi ZH..  (2020)  Small-Molecule Fms-like Tyrosine Kinase 3 Inhibitors: An Attractive and Efficient Method for the Treatment of Acute Myeloid Leukemia.,  63  (21.0): [PMID:32659083] [10.1021/acs.jmedchem.0c00696]

49. Lindberg MF, Deau E, Arfwedson J, George N, George P, Alfonso P, Corrionero A, Meijer L..  (2023)  Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases.,  66  (6): [PMID:36876904] [10.1021/acs.jmedchem.2c02068]

50. Liang X, Wang B, Chen C, Wang A, Hu C, Zou F, Yu K, Liu Q, Li F, Hu Z, Lu T, Wang J, Wang L, Weisberg EL, Li L, Xia R, Wang W, Ren T, Ge J, Liu J, Liu Q..  (2019)  Discovery of N-(4-(6-Acetamidopyrimidin-4-yloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide (CHMFL-FLT3-335) as a Potent FMS-like Tyrosine Kinase 3 Internal Tandem Duplication (FLT3-ITD) Mutant Selective Inhibitor for Acute Myeloid Leukemia.,  62  (2): [PMID:30565931] [10.1021/acs.jmedchem.8b01594]

51. Institute for Molecular Medicine Finland - High Throughput Biomedicine Unit.  (2023)  ECBD screening data for assay EOS300108,  [10.6019/EOS300108]

52. European Medicines Agency, 

Source

Source(16):

• Scientific Literature
• Sanger Institute Genomics of Drug Sensitivity in Cancer
• PubChem BioAssays
• Clinical Candidates
• FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book)
• USP Dictionary of USAN and International Drug Names
• K4DD Project
• Patent Bioactivity Data
• WHO Anatomical Therapeutic Chemical Classification
• British National Formulary
• Kuster lab chemical proteomics drug profiling
• SARS-CoV-2 Screening Data 2020-21
• IMI-CARE SARS-CoV-2 Data
• Fraunhofer HDAC6
• European Medicines Agency
• EU-OPENSCREEN dataset