Discovery of highly potent and ALK2/ALK 1 selective kinase inhibitors using DNA- encoded chemistry technology

被引:0
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作者
Jimmidi, Ravikumar [1 ,2 ]
Monsivais, Diana [1 ,2 ]
Ta, Hai Minh [1 ,2 ]
Sharma, Kiran L. [1 ,2 ]
Bohren, Kurt M. [1 ,2 ]
Chamakuri, Srinivas [1 ,2 ]
Liao, Zian [1 ,2 ,3 ]
Li, Feng [1 ,2 ,4 ]
Hakenjos, John M. [1 ,2 ]
Li, Jian - Yuan [1 ,2 ]
Mishina, Yuji [5 ]
Pan, Haichun
Qin, Xuan [1 ,2 ]
Robers, Matthew B. [6 ]
Sankaran, Banumathi [7 ]
Tan, Zhi [1 ,2 ]
Tang, Suni [1 ,2 ]
Vasquez, Yasmin M. [1 ,2 ]
Wilkinson, Jennifer [6 ]
Young, Damian W. [1 ,2 ,8 ]
Palmer, Stephen S. [1 ,2 ]
Mackenzie, Kevin R. [1 ,2 ,8 ]
Kim, Choel [1 ,2 ,8 ]
Matzuk, Martin M. [1 ,2 ,3 ,4 ,8 ]
机构
[1] Baylor Coll Med, Ctr Drug Discovery, Houston, TX 77030 USA
[2] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA
[3] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
[4] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
[5] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA
[6] Promega Corp, Madison, WI 53711 USA
[7] Lawrence Berkeley Natl Lab, Berkeley Ctr Struct Biol, Mol Biophys & Integrated Bioimaging, Berkeley, CA 94720 USA
[8] Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Pharmacol, Houston, TX 77030 USA
关键词
DEL; kinase inhibitors; X- ray Crystallography; FIBRODYSPLASIA OSSIFICANS PROGRESSIVA; TRANSFORMING GROWTH FACTOR-BETA-1; CHEMICAL LIBRARIES; ACVR1; MUTATIONS; BMP RECEPTOR; PROTEIN; BINDING;
D O I
10.1073/pnas.2413108121
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Activin receptor type 1 (ACVR1; ALK2) and activin receptor like type 1 (ACVRL1; ALK1) are transforming growth factor beta family receptors that integrate extracellular signals of bone morphogenic proteins (BMPs) and activins into Mothers Against Decapentaplegichomolog 1/5 (SMAD1/SMAD5) signaling complexes. Several activating mutations in ALK2 are implicated in fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine gliomas, and ependymomas. The ALK2 R206H mutation is also present in a subset of endometrial tumors, melanomas, non-small lung cancers, and colorectal cancers, and ALK2 expression is elevated in pancreatic cancer. Using DNA- encoded chemistry technology, we screened 3.94 billion unique compounds from our diverse DNA- encoded chemical libraries (DECLs) against the kinase domain of ALK2. Off- DNA synthesis of DECL hits and biochemical validation revealed nanomolar potent ALK2 inhibitors. Further structure-activity relationship studies yielded center for drug discovery (CDD)-2789, a potent [NanoBRET (NB) cell IC50: 0.54 mu M] and metabolically stable analog with good pharmacological profile. Crystal structures of ALK2 bound with CDD-2281, CDD-2282, or CDD-2789 show that these inhibitors bind the active site through Van der Waals interactions and solvent- mediated hydrogen bonds. CDD-2789 exhibits high selectivity toward ALK2/ALK1 in KINOMEscan analysis and NB K192 assay. In cell- based studies, ALK2 inhibitors effectively attenuated activin A and BMP- induced Phosphorylated SMAD1/5 activation in fibroblasts from individuals with FOP in a dose- dependent manner. Thus, CDD-2789 is a valuable tool compound for further investigation of the biological functions of ALK2 and ALK1 and the therapeutic potential of specific inhibition of ALK2.
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页数:11
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