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

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

doi:10.1016/j.ejmech.2023.115246

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

Journal Article · Fri Mar 03 23:00:00 EST 2023 · European Journal of Medicinal Chemistry

DOI:https://doi.org/10.1016/j.ejmech.2023.115246· OSTI ID:2423439

Koravovic, Mladen ^[1]; Mayasundari, Anand ^[2]; Tasic, Gordana ^[1]; Keramatnia, Fatemeh ^[2]; Stachowski, Timothy R. ^[2]; Cui, Huarui ^[3]; Chai, Sergio C. ^[2]; Jonchere, Barbara ^[2]; Yang, Lei ^[2]; Li, Yong ^[2]; Fu, Xiang ^[2]; Hiltenbrand, Ryan ^[2]; Paul, Leena ^[2]; Mishra, Vibhor ^[2]; Klco, Jeffery M. ^[2]; Roussel, Martine F. ^[2]; Pomerantz, William CK. ^[3]; Fischer, Marcus ^[2]; Rankovic, Zoran ^[2]; Savic, Vladimir ^[1]

Univ. of Belgrade (Serbia)
St. Jude Children's Research Hospital, Memphis, TN (United States)
Univ. of Minnesota, Minneapolis, MN (United States)

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. Finally, our study led to the discovery of potent and orally bioavailable BET inhibitor 1q (SJ1461) as a promising candidate for further development.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2423439

Journal Information:: European Journal of Medicinal Chemistry, Journal Name: European Journal of Medicinal Chemistry Vol. 251; ISSN 0223-5234

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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