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

• 成果类型: Article
• 署名作者: Jimmidi, Ravikumar; Monsivais, Diana; Ta, Hai Minh; Sharma, Kiran L.; Bohren, Kurt M.; Chamakuri, Srinivas; Liao, Zian; Li, Feng; Hakenjos, John M.; Li, Jian - Yuan; Mishina, Yuji; Pan, Haichun; Qin, Xuan; Robers, Matthew B.; Sankaran, Banumathi; Tan, Zhi; Tang, Suni; Vasquez, Yasmin M.; Wilkinson, Jennifer; Young, Damian W.; Palmer, Stephen S.; Mackenzie, Kevin R.; Kim, Choel; Matzuk, Martin M.
• 署名单位: Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; University of Michigan System; University of Michigan; Promega Corporation; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; Baylor College of Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12043
• DOI: 10.1073/pnas.2413108121
• 发表日期: 2024-11-19
• 关键词: fibrodysplasia ossificans progressiva; transforming growth factor-beta-1; chemical libraries; acvr1 mutations; bmp receptor; protein; binding

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.