ACS Medicinal Chemistry Letters, volume 14, issue 2, pages 199-210
Discovery of OICR12694: A Novel, Potent, Selective, and Orally Biovailable BCL6 BTB Inhibitor
Ahmed Mamai
1
,
Anh M Chau
1
,
Brian J. WILSON
1
,
Iain D Watson
1
,
Babu B Joseph
1
,
Pandiaraju R Subramanian
1
,
Monzur M Morshed
1
,
Justin A Morin
1
,
Michael A Prakesch
1
,
Tianbao Lu
2
,
Pete Connolly
2
,
Douglas A. Kuntz
3
,
Neil C. Pomroy
3
,
Gennady Poda
1, 4
,
Kong Nguyen
1
,
RICHARD MARCELLUS
1
,
Graig Strathdee
1
,
Brigitte Theriault
1
,
Ratheesh Subramaniam
1
,
Mohammed Mohammed
1
,
Ayome Abibi
1
,
Manuel CHAN
1
,
Jeffrey Winston
1
,
Taira Kiyota
1
,
Elijus Undzys
1
,
Ahmed Aman
1, 4
,
Nigel Austin
2
,
Marc Du Jardin
2
,
Kathryn Packman
2
,
Ulrike Phillippar
5
,
Riccardo Attar
2
,
James Edwards
2
,
Jeff Omeara
1
,
David E Uehling
1
,
Rima Al Awar
1, 6, 7
,
Gilbert G Privé
3, 8, 9
,
Methvin B Isaac
1
1
Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada
|
2
Janssen Research & Development, LLC, 1400 McKean Road, Spring House, Pennsylvania19477, United States
|
5
Janssen Research & Development, Turnhoutseweg 30, B-2340Beerse, Belgium
|
7
Publication type: Journal Article
Publication date: 2023-01-12
Journal:
ACS Medicinal Chemistry Letters
Quartile SCImago
Q1
Quartile WOS
Q2
SJR: 0.883
CiteScore: 7.3
Impact factor: 3.5
ISSN: 19485875
Organic Chemistry
Drug Discovery
Biochemistry
Abstract
B cell lymphoma 6 (BCL6), a highly regulated transcriptional repressor, is deregulated in several forms of non-Hodgkin lymphoma (NHL), most notably in diffuse large B-cell lymphoma (DLBCL). The activities of BCL6 are dependent on protein–protein interactions with transcriptional co-repressors. To find new therapeutic interventions addressing the needs of patients with DLBCL, we initiated a program to identify BCL6 inhibitors that interfere with co-repressor binding. A virtual screen hit with binding activity in the high micromolar range was optimized by structure-guided methods, resulting in a novel and highly potent inhibitor series. Further optimization resulted in the lead candidate 58 (OICR12694/JNJ-65234637), a BCL6 inhibitor with low nanomolar DLBCL cell growth inhibition and an excellent oral pharmacokinetic profile. Based on its overall favorable preclinical profile, OICR12694 is a highly potent, orally bioavailable candidate for testing BCL6 inhibition in DLBCL and other neoplasms, particularly in combination with other therapies.
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Mamai A. et al. Discovery of OICR12694: A Novel, Potent, Selective, and Orally Biovailable BCL6 BTB Inhibitor // ACS Medicinal Chemistry Letters. 2023. Vol. 14. No. 2. pp. 199-210.
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Mamai A., Chau A. M., WILSON B. J., Watson I. D., Joseph B. B., Subramanian P. R., Morshed M. M., Morin J. A., Prakesch M. A., Lu T., Connolly P., Kuntz D. A., Pomroy N. C., Poda G., Nguyen K., MARCELLUS R., Strathdee G., Theriault B., Subramaniam R., Mohammed M., Abibi A., CHAN M., Winston J., Kiyota T., Undzys E., Aman A., Austin N., Du Jardin M., Packman K., Phillippar U., Attar R., Edwards J., Omeara J., Uehling D. E., Al Awar R., Privé G. G., Isaac M. B. Discovery of OICR12694: A Novel, Potent, Selective, and Orally Biovailable BCL6 BTB Inhibitor // ACS Medicinal Chemistry Letters. 2023. Vol. 14. No. 2. pp. 199-210.
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TY - JOUR
DO - 10.1021/acsmedchemlett.2c00502
UR - https://doi.org/10.1021/acsmedchemlett.2c00502
TI - Discovery of OICR12694: A Novel, Potent, Selective, and Orally Biovailable BCL6 BTB Inhibitor
T2 - ACS Medicinal Chemistry Letters
AU - Mamai, Ahmed
AU - Chau, Anh M
AU - WILSON, Brian J.
AU - Watson, Iain D
AU - Joseph, Babu B
AU - Subramanian, Pandiaraju R
AU - Morshed, Monzur M
AU - Morin, Justin A
AU - Prakesch, Michael A
AU - Lu, Tianbao
AU - Connolly, Pete
AU - Kuntz, Douglas A.
AU - Pomroy, Neil C.
AU - Poda, Gennady
AU - Nguyen, Kong
AU - MARCELLUS, RICHARD
AU - Strathdee, Graig
AU - Theriault, Brigitte
AU - Subramaniam, Ratheesh
AU - Mohammed, Mohammed
AU - Abibi, Ayome
AU - CHAN, Manuel
AU - Winston, Jeffrey
AU - Kiyota, Taira
AU - Undzys, Elijus
AU - Aman, Ahmed
AU - Austin, Nigel
AU - Du Jardin, Marc
AU - Packman, Kathryn
AU - Phillippar, Ulrike
AU - Attar, Riccardo
AU - Edwards, James
AU - Omeara, Jeff
AU - Uehling, David E
AU - Al Awar, Rima
AU - Privé, Gilbert G
AU - Isaac, Methvin B
PY - 2023
DA - 2023/01/12
PB - American Chemical Society (ACS)
SP - 199-210
IS - 2
VL - 14
SN - 1948-5875
ER -
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@article{2023_Mamai,
author = {Ahmed Mamai and Anh M Chau and Brian J. WILSON and Iain D Watson and Babu B Joseph and Pandiaraju R Subramanian and Monzur M Morshed and Justin A Morin and Michael A Prakesch and Tianbao Lu and Pete Connolly and Douglas A. Kuntz and Neil C. Pomroy and Gennady Poda and Kong Nguyen and RICHARD MARCELLUS and Graig Strathdee and Brigitte Theriault and Ratheesh Subramaniam and Mohammed Mohammed and Ayome Abibi and Manuel CHAN and Jeffrey Winston and Taira Kiyota and Elijus Undzys and Ahmed Aman and Nigel Austin and Marc Du Jardin and Kathryn Packman and Ulrike Phillippar and Riccardo Attar and James Edwards and Jeff Omeara and David E Uehling and Rima Al Awar and Gilbert G Privé and Methvin B Isaac},
title = {Discovery of OICR12694: A Novel, Potent, Selective, and Orally Biovailable BCL6 BTB Inhibitor},
journal = {ACS Medicinal Chemistry Letters},
year = {2023},
volume = {14},
publisher = {American Chemical Society (ACS)},
month = {jan},
url = {https://doi.org/10.1021/acsmedchemlett.2c00502},
number = {2},
pages = {199--210},
doi = {10.1021/acsmedchemlett.2c00502}
}
Cite this
MLA
Copy
Mamai, Ahmed, et al. “Discovery of OICR12694: A Novel, Potent, Selective, and Orally Biovailable BCL6 BTB Inhibitor.” ACS Medicinal Chemistry Letters, vol. 14, no. 2, Jan. 2023, pp. 199-210. https://doi.org/10.1021/acsmedchemlett.2c00502.