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.
Keywords:
Amides / BET inhibitors / JQ1
Source:
European Journal of Medicinal Chemistry, 2023, 251
Publisher:
Elsevier Masson s.r.l.
Funding / projects:
ALSAC and R35GM142772 (to MF)
R35GM140837 (to WCKP)
Crystallographic data were collected at
Southeast Regional Collaborative Access Team (SER-CAT) 22-ID beam-
line at the Advanced Photon Source, Argonne National Laboratory.
SER-CAT is supported by its member institutions, and equipment grants
(S10_RR25528, S10_RR028976 and S10_OD027000) from the National
Institutes of Health.
The Advanced Photon Source was supported
by the U. S. Department of Energy, Office of Science, Office of Basic
Energy Sciences, under Contract No. W-31-109-Eng-38
The Science fund of the Republic of Serbia: program, Diaspora
TY - JOUR
AU - Koravović, Mladen
AU - Mayasundari, Anand
AU - Tasić, Gordana
AU - Keramatnia, F.
AU - Stachowski, Timothy R.
AU - Cui, Huarui
AU - Chai, Sergio C.
AU - Jonchere, Barbara
AU - Yang, Lei
AU - Li, Yong
AU - Fu, Xiang
AU - Hiltenbrand, Ryan
AU - Paul, Leena
AU - Mishra, Vibhor
AU - Klco, Jeffery M.
AU - Roussel, Martine F.
AU - Pomerantz, William CK.
AU - Fischer, Marcus
AU - Ranković, Zoran
AU - Savić, Vladimir
PY - 2023
UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4513
AB - 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.
PB - Elsevier Masson s.r.l.
T2 - European Journal of Medicinal Chemistry
T1 - From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors
VL - 251
DO - 10.1016/j.ejmech.2023.115246
ER -
@article{
author = "Koravović, Mladen and Mayasundari, Anand and Tasić, Gordana and Keramatnia, F. and Stachowski, Timothy R. and Cui, Huarui and Chai, Sergio C. and Jonchere, Barbara and Yang, Lei and Li, Yong and Fu, Xiang and Hiltenbrand, Ryan and Paul, Leena and Mishra, Vibhor and Klco, Jeffery M. and Roussel, Martine F. and Pomerantz, William CK. and Fischer, Marcus and Ranković, Zoran and Savić, Vladimir",
year = "2023",
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.",
publisher = "Elsevier Masson s.r.l.",
journal = "European Journal of Medicinal Chemistry",
title = "From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors",
volume = "251",
doi = "10.1016/j.ejmech.2023.115246"
}
Koravović, M., Mayasundari, A., Tasić, 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., Ranković, Z.,& Savić, V.. (2023). From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors. in European Journal of Medicinal Chemistry
Elsevier Masson s.r.l.., 251.
https://doi.org/10.1016/j.ejmech.2023.115246
Koravović M, Mayasundari A, Tasić 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 WC, Fischer M, Ranković Z, Savić V. From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors. in European Journal of Medicinal Chemistry. 2023;251.
doi:10.1016/j.ejmech.2023.115246 .
Koravović, Mladen, Mayasundari, Anand, Tasić, Gordana, Keramatnia, F., 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, Ranković, Zoran, Savić, Vladimir, "From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors" in European Journal of Medicinal Chemistry, 251 (2023),
https://doi.org/10.1016/j.ejmech.2023.115246 . .
