Tesirine

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Tesirine.png2D chemical structure of 1595275-62-9

Tesirine

Molecular Formula: C75H101N9O23
Molecular Weight: 1496.673 g/mol

UNII-8DVQ435K46;

CAS 1595275-62-9

(11S,11aS)-4-((2S,5S)-37-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-5-isopropyl-2-methyl-4,7,35-trioxo-10,13,16,19,22,25,28,31-octaoxa-3,6,34-triazaheptatriacontanamido)benzyl 11-hydroxy-7-methoxy-8-((5-(((S)-7-methoxy-2-methyl-5-oxo-5,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)pentyl)oxy)-2-methyl-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylate 

SG3249, Tesirine

[4-[[(2S)-2-[[(2S)-2-[3-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]-3-methylbutanoyl]amino]propanoyl]amino]phenyl]methyl (6S,6aS)-3-[5-[[(6aS)-2-methoxy-8-methyl-11-oxo-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]pentoxy]-6-hydroxy-2-methoxy-8-methyl-11-oxo-6a,7-dihydro-6H-pyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate

PATENT

WO 2014057074

In 2012, tesirine (SG3249) was developed by Spirogen, as a drug linker combining a set of desired properties: fast and straightforward conjugation to antibody cysteines by maleimide Michael addition, good solubility in aqueous/DMSO (90/10) systems, and a traceless cleavable linker system delivering the highly potent pyrrolobenzodiazepine (PBD) DNA cross-linker SG3199

Image result for tesirine

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CLIP

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CLIP

Scale-up Synthesis of Tesirine

 SpirogenQMB Innovation Centre42 New Road, E1 2AX London, United Kingdom
§ PharmaronNo. 6, Taihe Road, BDA, Beijing, 100176, People’s Republic of China
 Lonza AGRottenstrasse 6, CH – 3930 Visp, Switzerland
# Novasep Ltd1 Rue Démocrite, 72000 Le Mans, France
 Early Chemical Development, Pharmaceutical SciencesIMED Biotech UnitAstraZeneca, Macclesfield, United Kingdom
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00205
Abstract Image

This work describes the enabling synthesis of tesirine, a pyrrolobenzodiazepine antibody–drug conjugate drug-linker. Over the course of four synthetic campaigns, the discovery route was developed and scaled up to provide a robust manufacturing process. Early intermediates were produced on a kilogram scale and at high purity, without chromatography. Midstage reactions were optimized to minimize impurity formation. Late stage material was produced and purified using a small number of key high-pressure chromatography steps, ultimately resulting in a 169 g batch after 34 steps. At the time of writing, tesirine is the drug-linker component of eight antibody–drug conjugates in multiple clinical trials, four of them pivotal

 CLIP

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

QMB Innovation Centre, Spirogen, 42 New Road, E1 2AX London, U.K.
ACS Med. Chem. Lett.20167 (11), pp 983–987
DOI: 10.1021/acsmedchemlett.6b00062
Publication Date (Web): May 24, 2016
Copyright © 2016 American Chemical Society
This article is part of the Antibody-Drug Conjugates and Bioconjugates special issue.
Abstract Image

Pyrrolobenzodiazepine dimers are an emerging class of warhead in the field of antibody–drug conjugates (ADCs). Tesirine (SG3249) was designed to combine potent antitumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics. One of the reactive imines was capped with a cathepsin B-cleavable valine-alanine linker. A robust synthetic route was developed to allow the production of tesirine on clinical scale, employing a flexible, convergent strategy. Tesirine was evaluated in vitro both in stochastic and engineered ADC constructs and was confirmed as a potent and versatile payload. The conjugation of tesirine to anti-DLL3 rovalpituzumab has resulted in rovalpituzumab-tesirine (Rova-T), currently under evaluation for the treatment of small cell lung cancer.

https://cdn-pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.6b00062/suppl_file/ml6b00062_si_001.pdf

SG3249 (tesirine) (860 mg, 73% over 2 steps). LC/MS, method 2, 2.65 min (ES+) m/z (relative intensity) 1496.78 ([M+H] +. , 20). [] 24 D = +262 (c = 0.056, CHCl3).

1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.20 (d, J = 7.0 Hz, 1H), 8.03 (t, J = 5.6 Hz, 1H), 7.97 – 7.84 (m, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.32 (s, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.10 – 6.96 (m, 3H), 6.84 (s, 1H), 6.79 – 6.57 (m, 4H), 5.59 (d, J = 9.4 Hz, 1H), 5.16 (d, J = 12.7 Hz, 1H), 4.81 (d, J = 12.4 Hz, 1H), 4.38 (t, J = 7.1 Hz, 1H), 4.32 – 4.17 (m, 2H), 4.17 – 4.07 (m, 1H), 4.07 – 3.87 (m, 3H), 3.80 (d, J = 14.2 Hz, 6H), 3.74 – 3.62 (m, 1H), 3.59 (t, J = 7.2 Hz, 4H), 3.55 – 3.42 (m, 28H), 3.35 (d, J = 5.2 Hz, 2H), 3.21 – 3.11 (m, 2H), 3.11 – 2.98 (m, 2H), 2.98 – 2.83 (m, 1H), 2.49 – 2.28 (m, 5H), 2.03 – 1.88 (m, 1H), 1.87 – 1.65 (m, 10H), 1.64 – 1.47 (m, 2H), 1.29 (t, J = 5.9 Hz, 3H), 0.85 (dd, J = 17.1, 6.7 Hz, 6H).

13C NMR (126 MHz, DMSO-d6) δ 171.55, 171.29, 171.16, 170.78, 169.91, 164.80, 162.52, 155.03, 150.25, 139.27, 134.99, 128.84, 123.13, 122.67, 121.76, 119.28, 111.93, 110.93, 86.05, 70.21, 70.16, 70.02, 69.95, 69.46, 68.93, 68.79, 67.39, 57.94, 56.16, 54.03, 49.49, 38.97, 38.89, 36.39, 34.53, 34.40, 31.04, 28.69, 28.65, 22.72, 19.60, 18.55, 18.37, 13.88, 13.82. HRMS (ESI) m/z Calc. C75H101N9O23 1495.70831 found 1495.70444.

FT-IR (ATR, cm‐1 ) 3311, 2911, 2871, 1706, 1643, 1623, 1601, 1512, 1435, 1411, 1243, 1213, 1094, 1075, 946, 827, 747, 695, 664.

Patent ID

Title

Submitted Date

Granted Date

US2015297746 PYRROLOBENZODIAZEPINE-ANTIBODY CONJUGATES
2013-10-11
2015-10-22
US2017267778 HUMANIZED ANTI-TN-MUC1 ANTIBODIES AND THEIR CONJUGATES
2015-04-15
Patent ID

Title

Submitted Date

Granted Date

US2015283258 PYRROLOBENZODIAZEPINE – ANTI-PSMA ANTIBODY CONJUGATES
2013-10-11
2015-10-08
US2015283262 PYRROLOBENZODIAZEPINE-ANTIBODY CONJUGATES
2013-10-11
2015-10-08
US2015283263 PYRROLOBENZODIAZEPINE-ANTIBODY CONJUGATES
2013-10-11
2015-10-08
US2016106861 AXL ANTIBODY-DRUG CONJUGATE AND ITS USE FOR THE TREATMENT OF CANCER
2014-04-28
2016-04-21
US2014127239 PYRROLOBENZODIAZEPINES AND CONJUGATES THEREOF
2013-10-11
2014-05-08
Patent ID

Title

Submitted Date

Granted Date

US2017320960 NOVEL ANTI-MFI2 ANTIBODIES AND METHODS OF USE
2015-09-04
US2016015828 NOVEL ANTIBODY CONJUGATES AND USES THEREOF
2014-02-21
2016-01-21
US2015265722 PYRROLOBENZODIAZEPINE-ANTI-CD22 ANTIBODY CONJUGATES
2013-10-11
2015-09-24
US2015273077 PYRROLOBENZODIAZEPINE-ANTI-HER2 ANTIBODY CONJUGATES
2013-10-11
2015-10-01
US2015273078 PYRROLOBENZODIAZEPINE-ANTI-PSMA ANTIBODY CONJUGATES
2013-10-11
2015-10-01

.//////////Tesirine, SG3249, SG 3249

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