From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors

Mladen Koravovic; Anand Mayasundari; Gordana Tasic; Fatemeh Keramatnia; Timothy R. Stachowski; Huarui Cui; Sergio C. Chai; Barbara Jonchere; Lei Yang; Yong Li; Xiang Fu; Ryan Hiltenbrand; Leena Paul; Vibhor Mishra; Jeffery M. Klco; Martine F. Roussel; William CK Pomerantz; Marcus Fischer; Zoran Rankovic; Vladimir Savic

doi:10.1016/j.ejmech.2023.115246

From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors

Mladen Koravovic, Anand Mayasundari, Gordana Tasic, Fatemeh Keramatnia, Timothy R. Stachowski, Huarui Cui, Sergio C. Chai, Barbara Jonchere, Lei Yang, Yong Li, Xiang Fu, Ryan Hiltenbrand, Leena Paul, Vibhor Mishra, Jeffery M. Klco, Martine F. Roussel, William CK Pomerantz, Marcus Fischer, Zoran Rankovic, Vladimir Savic

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Abstract

An X-ray structure of a CLICK chemistry-based BET PROTAC bound to BRD2(BD2) inspired synthesis of JQ1 derived heterocyclic amides. This effort led to the discovery of potent BET inhibitors displaying overall improved profiles when compared to JQ1 and birabresib. A thiadiazole derived 1q (SJ1461) displayed excellent BRD4 and BRD2 affinity and high potency in the panel of acute leukaemia and medulloblastoma cell lines. A structure of 1q co-crystalised with BRD4-BD1 revealed polar interactions with the AZ/BC loops, in particular with Asn140 and Tyr139, rationalising the observed affinity improvements. In addition, exploration of pharmacokinetic properties of this class of compounds suggest that the heterocyclic amide moiety improves drug-like features. Our study led to the discovery of potent and orally bioavailable BET inhibitor 1q (SJ1461) as a promising candidate for further development.

Original language	English (US)
Article number	115246
Journal	European Journal of Medicinal Chemistry
Volume	251
DOIs	https://doi.org/10.1016/j.ejmech.2023.115246
State	Published - May 5 2023
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Masson SAS

Keywords

Amides
BET inhibitors
JQ1

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Koravovic, M., Mayasundari, A., Tasic, G., Keramatnia, F., Stachowski, T. R., Cui, H., Chai, S. C., Jonchere, B., Yang, L., Li, Y., Fu, X., Hiltenbrand, R., Paul, L., Mishra, V., Klco, J. M., Roussel, M. F., Pomerantz, W. CK., Fischer, M., Rankovic, Z., & Savic, V. (2023). From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors. European Journal of Medicinal Chemistry, 251, Article 115246. https://doi.org/10.1016/j.ejmech.2023.115246

Koravovic, M, Mayasundari, A, Tasic, G, Keramatnia, F, Stachowski, TR, Cui, H, Chai, SC, Jonchere, B, Yang, L, Li, Y, Fu, X, Hiltenbrand, R, Paul, L, Mishra, V, Klco, JM, Roussel, MF, Pomerantz, WCK, Fischer, M, Rankovic, Z & Savic, V 2023, 'From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors', European Journal of Medicinal Chemistry, vol. 251, 115246. https://doi.org/10.1016/j.ejmech.2023.115246

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AU - Stachowski, Timothy R.

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AU - Yang, Lei

AU - Li, Yong

AU - Fu, Xiang

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AU - Paul, Leena

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AU - Klco, Jeffery M.

AU - Roussel, Martine F.

AU - Pomerantz, William CK

AU - Fischer, Marcus

AU - Rankovic, Zoran

AU - Savic, Vladimir

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From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors

Abstract

Bibliographical note

Keywords

UN SDGs

Access

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