From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors
Само за регистроване кориснике
2023
Аутори
Koravović, MladenMayasundari, 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
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
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.
Кључне речи:
Amides / BET inhibitors / JQ1Извор:
European Journal of Medicinal Chemistry, 2023, 251Издавач:
- Elsevier
Финансирање / пројекти:
- 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
- Grant no: 6463913
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200161 (Универзитет у Београду, Фармацеутски факултет) (RS-MESTD-inst-2020-200161)
DOI: 10.1016/j.ejmech.2023.115246
ISSN: 0223-5234
PubMed: 36898329
WoS: 000952151800001
Scopus: 2-s2.0-85149446323
Институција/група
PharmacyTY - 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 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", 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., 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 . .