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

Eur J Med Chem. 2023 May 5:251:115246. doi: 10.1016/j.ejmech.2023.115246. Epub 2023 Mar 4.

Authors

Mladen Koravovic¹, Anand Mayasundari², Gordana Tasic¹, Fatemeh Keramatnia², Timothy R Stachowski², Huarui Cui³, Sergio C Chai², Barbara Jonchere⁴, Lei Yang², Yong Li², Xiang Fu², Ryan Hiltenbrand⁵, Leena Paul⁶, Vibhor Mishra⁵, Jeffery M Klco⁵, Martine F Roussel⁴, William Ck Pomerantz³, Marcus Fischer², Zoran Rankovic⁷, Vladimir Savic⁸

Affiliations

¹ University of Belgrade, Faculty of Pharmacy, Department of Organic Chemistry, Vojvode Stepe 450, 11221, Belgrade, Serbia.
² Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
³ Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, MN, 55455, United States.
⁴ Department of Tumour Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
⁵ Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
⁶ Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
⁷ Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. Electronic address: zoran.rankovic@stjude.org.
⁸ University of Belgrade, Faculty of Pharmacy, Department of Organic Chemistry, Vojvode Stepe 450, 11221, Belgrade, Serbia. Electronic address: vladimir.savic@pharmacy.bg.ac.rs.

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.

Keywords: Amides; BET inhibitors; JQ1.

MeSH terms

Cell Cycle Proteins / metabolism
Cell Line
Nuclear Proteins* / metabolism
Transcription Factors* / metabolism

Substances

Nuclear Proteins
Transcription Factors
Cell Cycle Proteins

Abstract

MeSH terms

Substances

Grants and funding