Journal ArticleDOI
Development of Dimethylisoxazole-Attached Imidazo[1,2-a]pyridines as Potent and Selective CBP/P300 Inhibitors
Alex Muthengi,Virangika K. Wimalasena,Hailemichael O. Yosief,M.J. Bikowitz,Logan H. Sigua,Tingjian Wang,Deyao Li,Zied Gaieb,Gagan Dhawan,Shuai Liu,Jon Erickson,Rommie E. Amaro,Ernst Schönbrunn,Jun Qi,Wei Zhang +14 more
Reads0
Chats0
TLDR
In this article, a two-step synthetic route for dimethylisoxazole-attached imidazo[1,2-a]pyridine scaffold-containing inhibitors was developed, which enabled high-throughput synthesis of compounds designed by molecular modeling.Abstract:
The use of epigenetic bromodomain inhibitors as anticancer therapeutics has transitioned from targeting bromodomain extraterminal domain (BET) proteins into targeting non-BET bromodomains. The two most relevant non-BET bromodomain oncology targets are cyclic AMP response element-binding protein (CBP) and E1A binding protein P300 (EP300). To explore the growing CBP/EP300 interest, we developed a highly efficient two-step synthetic route for dimethylisoxazole-attached imidazo[1,2-a]pyridine scaffold-containing inhibitors. Our efficient two-step reactions enabled high-throughput synthesis of compounds designed by molecular modeling, which together with structure-activity relationship (SAR) studies facilitated an overarching understanding of selective targeting of CBP/EP300 over non-BET bromodomains. This led to the identification of a new potent and selective CBP/EP300 bromodomain inhibitor, UMB298 (compound 23, CBP IC50 72 nM and bromodomain 4, BRD4 IC50 5193 nM). The SAR we established is in good agreement with literature-reported CBP inhibitors, such as CBP30, and demonstrates the advantage of utilizing our two-step approach for inhibitor development of other bromodomains.read more
Citations
More filters
Journal ArticleDOI
Synthesis of Spiro[chromene-imidazo[1,2-a]pyridin]-3'-imines via 6-exo-dig Cyclization Reaction.
Behrouz Nayebzadeh,Kamran Amiri,Hormoz Khosravi,Saber Mirzaei,Frank Rominger,Dmitry Dar'in,Mikhail Krasavin,Hamid Reza Bijanzadeh,Saeed Balalaie,Saeed Balalaie +9 more
TL;DR: A transition-metal-free postmodification of the Groebke-Blackburn-Bienayme (GBB) reaction for the synthesis of spiro[chromene-imidazo[1,2-a]pyridin]-3'-imine was discovered in this paper.
Journal ArticleDOI
Ag2O/squaramide cocatalyzed asymmetric interrupted Barton-Zard reaction of 8-nitroimidazo[1,2-a]pyridines
Katrin Kurz,Jelte van der Vaart +1 more
TL;DR: In this paper , an asymmetric interrupted Barton-Zard reaction of electron-deficient imidazo[1,2-a]pyridines with α-substituted isocyanoacetates was reported.
Journal ArticleDOI
Recent Advances on Small-Molecule Bromodomain-Containing Histone Acetyltransferase Inhibitors.
Mingxia Liu,Kaiyao Zhang,Qinjue Li,Haiying Pang,Zhaoping Pan,Xiaowei Huang,Lian Wang,Fengbo Wu,Gu He +8 more
TL;DR: In this article , the development of BRD-containing HATs as chemical probes is useful for understanding the specific biological roles of BRDs in diseases and drug discovery, and progress in BRD inhibitors/chemical probes and proteolysis targeting chimeras in terms of drug design, biological activity and disease application are summarized.
Journal ArticleDOI
The Role of CREBBP/EP300 and Its Therapeutic Implications in Hematological Malignancies
TL;DR: In this paper , the role of CREBBP/EP300 in normal hematopoiesis and the potential future therapeutic implications of related inhibitors were discussed from several aspects.
Journal ArticleDOI
Copper-catalyzed three-component reaction to synthesize polysubstituted imidazo[1,2-a]pyridines
TL;DR: An efficient three-component one-pot and operationally simple cascade of 2-aminopyridines with sulfonyl azides and terminal ynones is reported, providing a variety of polysubstituted imidazo[1,2-a]pyridine derivatives in moderate to excellent yields.
References
More filters
Journal ArticleDOI
Features and development of Coot.
TL;DR: Coot is a molecular-graphics program designed to assist in the building of protein and other macromolecular models and the current state of development and available features are presented.
Journal ArticleDOI
Integration, scaling, space‐group assignment and post‐refinement
TL;DR: The working principles of important steps in processing rotation data are described as employed by the program XDS.
Journal ArticleDOI
Cross-coupling reactions of organoboranes: an easy way to construct C-C bonds (Nobel Lecture).
Journal ArticleDOI
Histone recognition and large-scale structural analysis of the human bromodomain family.
Panagis Filippakopoulos,Sarah Picaud,Maria M. Mangos,T. Keates,Jean-Philippe Lambert,Dalia Barsyte-Lovejoy,I. Felletar,Rudolf Volkmer,Susanne Müller,Tony Pawson,Anne-Claude Gingras,Cheryl H. Arrowsmith,Cheryl H. Arrowsmith,Stefan Knapp,Stefan Knapp,Stefan Knapp +15 more
TL;DR: Bromodomains are protein interaction modules that specifically recognize ε-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks, and a structural mechanism for the simultaneous binding and recognition of diverse diacetyl-containing peptides by BRD4 is uncovered.
Journal ArticleDOI
Targeting bromodomains: epigenetic readers of lysine acetylation
TL;DR: Recent progress in the development of bromodomain inhibitors is highlighted, and their potential applications in drug discovery are highlighted.
Related Papers (5)
Discovery and Optimization of Small-Molecule Ligands for the CBP/p300 Bromodomains
Duncan Hay,Oleg Fedorov,Sarah Martin,Dean C. Singleton,Cynthia Tallant,Christopher Wells,Sarah Picaud,Martin Philpott,Octovia P. Monteiro,Catherine M. Rogers,Stuart J. Conway,Timothy P. C. Rooney,Anthony Tumber,Clarence Yapp,Panagis Filippakopoulos,Mark E. Bunnage,Susanne Müller,Stefan Knapp,Christopher J. Schofield,Paul Brennan +19 more