Design and Synthesis of Tesirine, a Clinical Antibody-Drug Conjugate Pyrrolobenzodiazepine Dimer Payload

ACS Medicinal Chemistry Letters

Volumn 7, Issue 11, 2016, Pages 983-987

  Tiberghien, Arnaud C ^a   Levy, Jean Noel ^a,b   Masterson, Luke A ^a   Patel, Neki V ^a   Adams, Lauren R ^a   Corbett, Simon ^a   Williams, David G ^a   Hartley, John A ^a   Howard, Philip W ^a  

^a ASTRAZENECA   (United Kingdom)

^b Stemcentrx   (United States)

Author keywords

antibody drug conjugates; Rova T; SG3249; talirine; Tesirine

Indexed keywords

ALANINE; ANTINEOPLASTIC AGENT; BENZODIAZEPINE DERIVATIVE; CATHEPSIN B; IMINE; PYRROLOBENZODIAZEPINE DERIVATIVE; ROVALPITUZUMAB TESIRINE; TESIRINE; UNCLASSIFIED DRUG; VALINE;

ANTINEOPLASTIC ACTIVITY; ARTICLE; DERIVATIZATION; DNA HELIX; DRUG CONJUGATION; DRUG DESIGN; DRUG POTENCY; DRUG SYNTHESIS; HUMAN; HUMAN CELL; HYDROPHOBICITY; IN VITRO STUDY; NITRATION; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; PROTEIN CLEAVAGE; RACEMIZATION; STEREOCHEMISTRY; SUZUKI REACTION; THERMODYNAMICS;

EID: 84994853897     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/acsmedchemlett.6b00062     Document Type: Article

References (33)

1. Leimgruber, W.; Stefanovic, V.; Schenker, F.; Karr, A.; Berger, J. Isolation and characterization of anthramycin, a new antitumor antibiotic J. Am. Chem. Soc. 1965, 87 (24) 5791-3 10.1021/ja00952a050
2. Tendler, M. D.; Korman, S. 'Refuin': A non-cytotoxic carcinostatic compound proliferated by a thermophilic actinomycete Nature 1963, 199, 501 10.1038/199501a0
3. Hartley, J. A. The development of pyrrolobenzodiazepines as antitumour agents Expert Opin. Invest. Drugs 2011, 20 (6) 733-44 10.1517/13543784.2011.573477
4. Kung Sutherland, M. S.; Walter, R. B.; Jeffrey, S. C.; Burke, P. J.; Yu, C.; Kostner, H.; Stone, I.; Ryan, M. C.; Sussman, D.; Lyon, R. P.; Zeng, W.; Harrington, K. H.; Klussman, K.; Westendorf, L.; Meyer, D.; Bernstein, I. D.; Senter, P. D.; Benjamin, D. R.; Drachman, J. G.; McEarchern, J. A. SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML Blood 2013, 122 (8) 1455-63 10.1182/blood-2013-03-491506
5. Chari, R. V.; Miller, M. L.; Widdison, W. C. Antibody-drug conjugates: an emerging concept in cancer therapy Angew. Chem., Int. Ed. 2014, 53 (15) 3796-827 10.1002/anie.201307628
6. Jeffrey, S. C.; Burke, P. J.; Lyon, R. P.; Meyer, D. W.; Sussman, D.; Anderson, M.; Hunter, J. H.; Leiske, C. I.; Miyamoto, J. B.; Nicholas, N. D.; Okeley, N. M.; Sanderson, R. J.; Stone, I. J.; Zeng, W.; Gregson, S. J.; Masterson, L.; Tiberghien, A. C.; Howard, P. W.; Thurston, D. E.; Law, C. L.; Senter, P. D. A potent anti-CD70 antibody-drug conjugate combining a dimeric pyrrolobenzodiazepine drug with site-specific conjugation technology Bioconjugate Chem. 2013, 24 (7) 1256-63 10.1021/bc400217g
7. A safety study of SGN-CD33A in AML patients. https://www.clinicaltrials.gov/ct2/show/NCT01902329.
8. Jeffrey, S. C.; Nguyen, M. T.; Andreyka, J. B.; Meyer, D. L.; Doronina, S. O.; Senter, P. D. Dipeptide-based highly potent doxorubicin antibody conjugates Bioorg. Med. Chem. Lett. 2006, 16 (2) 358-362 10.1016/j.bmcl.2005.09.081
9. Howard, P. W.; Chen, Z.; Gregson, S. J.; Masterson, L. A.; Tiberghien, A. C.; Cooper, N.; Fang, M.; Coffils, M. J.; Klee, S.; Hartley, J. A.; Thurston, D. E. Synthesis of a novel C2/C2′-aryl-substituted pyrrolo[2,1-c][1,4]benzodiazepine dimer prodrug with improved water solubility and reduced DNA reaction rate Bioorg. Med. Chem. Lett. 2009, 19 (22) 6463-6 10.1016/j.bmcl.2009.09.012
10. Hartley, J. A.; Hamaguchi, A.; Coffils, M.; Martin, C. R. H.; Suggitt, M.; Chen, Z.; Gregson, S. J.; Masterson, L. A.; Tiberghien, A. C.; Hartley, J. M.; Pepper, C.; Lin, T. T.; Fegan, C.; Thurston, D. E.; Howard, P. W. SG2285, a Novel C2-Aryl-Substituted Pyrrolobenzodiazepine Dimer Prodrug That Cross-links DNA and Exerts Highly Potent Antitumor Activity Cancer Res. 2010, 70 (17) 6849-6858 10.1158/0008-5472.CAN-10-0790
11. Gregson, S. J.; Howard, P. W.; Gullick, D. R.; Hamaguchi, A.; Corcoran, K. E.; Brooks, N. A.; Hartley, J. A.; Jenkins, T. C.; Patel, S.; Guille, M. J.; Thurston, D. E. Linker length modulates DNA cross-linking reactivity and cytotoxic potency of C8/C8′ ether-linked C2-exo-unsaturated pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimers J. Med. Chem. 2004, 47 (5) 1161-74 10.1021/jm030897l
12. Howard, P. W.; Kang, G.-D. Preparation, DNA crosslinking reactivity and antiproliferative activity of pyrrolobenzodiazepine dimers. WO2005085259A2, 2005.
13. Gregson, S. J.; Howard, P. W.; Hartley, J. A.; Brooks, N. A.; Adams, L. J.; Jenkins, T. C.; Kelland, L. R.; Thurston, D. E. Design, synthesis, and evaluation of a novel pyrrolobenzodiazepine DNA-interactive agent with highly efficient cross-linking ability and potent cytotoxicity J. Med. Chem. 2001, 44 (5) 737-48 10.1021/jm001064n
14. Kamal, A.; Ramesh, G.; Laxman, N.; Ramulu, P.; Srinivas, O.; Neelima, K.; Kondapi, A. K.; Sreenu, V. B.; Nagarajaram, H. A. Design, synthesis, and evaluation of new non-cross-Linking pyrrolobenzodiazepine dimers with efficient DNA binding ability and potent antitumor activity J. Med. Chem. 2002, 45 (21) 4679-4688 10.1021/jm020124h
15. Kolakowski, R. V.; Young, T. D.; Howard, P. W.; Jeffrey, S. C.; Senter, P. D. Synthesis of a C2-aryl-pyrrolo[2,1-c][1,4]benzodiazepine monomer enabling the convergent construction of symmetrical and non-symmetrical dimeric analogs Tetrahedron Lett. 2015, 56 (30) 4512-4515 10.1016/j.tetlet.2015.05.116
16. Althuis, T. H.; Hess, H. J. Synthesis and identification of the major metabolites of prazosin formed in dog and rat J. Med. Chem. 1977, 20 (1) 146-9 10.1021/jm00211a031
17. Howard, P. W. Preparation of pyrrolobenzodiazepine dimers and their conjugates with cell binding agents, especially pyrrolobenzodiazepine dimer drug linker antibody conjugates containing dipeptide linkers, and their use for treating proliferative diseases, particularly cancer. WO2014057074A1.
18. Howard, P. W.; Tiberghien, A. Process for the preparation of intermediates useful for the synthesis of pyrrolobenzodiazepine dimers. WO2013053872A1.
19. Mu, Y.; Gibbs, R. A. Coupling of isoprenoid triflates with organoboron nucleophiles: Synthesis of all-trans-geranylgeraniol Tetrahedron Lett. 1995, 36 (32) 5669-5672 10.1016/00404-0399(50)11193-
20. Masterson, L. A.; Spanswick, V. J.; Hartley, J. A.; Begent, R. H.; Howard, P. W.; Thurston, D. E. Synthesis and biological evaluation of novel pyrrolo[2,1-c][1,4]benzodiazepine prodrugs for use in antibody-directed enzyme prodrug therapy Bioorg. Med. Chem. Lett. 2006, 16 (2) 252-6 10.1016/j.bmcl.2005.10.017
21. Howard, P. W.; Masterson, L.; Tiberghien, A.; Flygare, J. A.; Gunzner, J. L.; Polakis, P.; Polson, A.; Raab, H. E.; Spencer, S. D. Preparation of pyrrolobenzodiazepine dimers and conjugates, especially pyrrolobenzodiazepine dimer drug linker conjugates containing peptide linkers, and their use for treating proliferative diseases including cancer. WO2011130598A1.
22. Wells, G.; Martin, C. R.; Howard, P. W.; Sands, Z. A.; Laughton, C. A.; Tiberghien, A.; Woo, C. K.; Masterson, L. A.; Stephenson, M. J.; Hartley, J. A.; Jenkins, T. C.; Shnyder, S. D.; Loadman, P. M.; Waring, M. J.; Thurston, D. E. Design, synthesis, and biophysical and biological evaluation of a series of pyrrolobenzodiazepine-poly(N-methylpyrrole) conjugates J. Med. Chem. 2006, 49 (18) 5442-61 10.1021/jm051199z
23. Corey, E. J.; Cho, H.; Rucker, C.; Hua, D. H. Studies with trialkylsilyltriflates: new syntheses and applications Tetrahedron Lett. 1981, 22 (36) 3455-3458 10.1016/S0040-4039(01)81930-4
24. Wang, B.; Sun, H. X.; Sun, Z. H. LiOAc-catalyzed chemoselective deprotection of aryl silyl ethers under mild conditions J. Org. Chem. 2009, 74 (4) 1781-4 10.1021/jo802472s
25. Kocienski, P. J. Protecting Groups, 3 rd ed.; Thieme: 2005; p 208.
26. Terauchi, T.; Tanaka, T.; Terauchi, T.; Morita, M.; Kimijima, K.; Sato, I.; Shoji, W.; Nakamura, Y.; Tsukada, T.; Tsunoda, T.; Hayashi, G.; Kanoh, N.; Nakata, M. Formal total synthesis of altohyrtin C (spongistatin 2). Part 2: Construction of fully elaborated ABCD and EF fragments Tetrahedron Lett. 2003, 44 (42) 7747-7751 10.1016/j.tetlet.2003.08.083
27. Deziel, R. Mild palladium (O)-catalyzed deprotection of allyl esters. A useful application in the synthesis of carbapenems and other B-lactam derivatives Tetrahedron Lett. 1987, 28 (38) 4371-4372 10.1016/S0040-4039(00)96512-2
28. Kurti, L.; Czako, B. Strategic Applications of Named Reactions in Organic Synthesis; Elsevier Academic Press: 2005; pp 458-9.
29. SC16LD6.5 in recurrent small cell lung cancer. https://clinicaltrials.gov/ct2/show/NCT01901653.
30. Saunders, L. R.; Bankovich, A. J.; Anderson, W. C.; Aujay, M. A.; Bheddah, S.; Black, K.; Desai, R.; Escarpe, P. A.; Hampl, J.; Laysang, A.; Liu, D.; Lopez-Molina, J.; Milton, M.; Park, A.; Pysz, M. A.; Shao, H.; Slingerland, B.; Torgov, M.; Williams, S. A.; Foord, O.; Howard, P.; Jassem, J.; Badzio, A.; Czapiewski, P.; Harpole, D. H.; Dowlati, A.; Massion, P. P.; Travis, W. D.; Pietanza, M. C.; Poirier, J. T.; Rudin, C. M.; Stull, R. A.; Dylla, S. J. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo Sci. Transl. Med. 2015, 7 (302) 302ra136 10.1126/scitranslmed.aac9459
31. Pietanza, M. C.; Spigel, D.; Bauer, T. M.; Ready, N. E.; Glisson, B. S.; Morgensztern, D.; Robert, F.; Salgia, R.; Kochendorfer, M.; Patel, M.; Strickland, D. K.; Govindan, R.; Burris, H. A.; Rudin, C. M.; Dylla, S. Safety, activity, and response durability assessment of single agent rovalpituzumab tesirine, a delta-like protein 3 (DLL3)-targeted antibody drug conjugate (ADC), in small cell lung cancer (SCLC) Eur. J. Cancer 2015, 51, S712 10.1016/S0959-8049(16)31931-1
32. Study of ADCT-301 in patients with relapsed or refractory Hodgkin and non-Hodgkin lymphoma. https://www.clinicaltrials.gov/ct2/show/NCT02432235.
33. Flynn, M.; Berkel, P.; Zammarchi, F.; Levy, J.; Tiberghien, A.; Masterson, L.; D'Hooge, F.; Adams, L.; Williams, D.; Howard, P.; Hartley, J., Pre-Clinical Activity of Adct-301, a novel pyrrolobenzodiazepine (PBD) dimer-containing antibody drug conjugate (ADC) targeting CD25-expressing hematological malignancies. In 56th ASH Annual Meeting and Exposition, San Francisco, 2014; p 4491.