9D8E
Crystal structure of the ACVR1 (ALK2) Kinase Domain in complex with inhibitor CDD-2789
This is a non-PDB format compatible entry.
Summary for 9D8E
| Entry DOI | 10.2210/pdb9d8e/pdb |
| Descriptor | Activin receptor type-1, GLYCEROL, 1-cyclobutyl-N-[3-(dimethylamino)propyl]-2-(3,4,5-trimethoxyphenyl)-1H-1,3-benzimidazole-6-carboxamide, ... (5 entities in total) |
| Functional Keywords | kinase, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 76861.66 |
| Authors | |
| Primary citation | Jimmidi, R.,Monsivais, D.,Ta, H.M.,Sharma, K.L.,Bohren, K.M.,Chamakuri, S.,Liao, Z.,Li, F.,Hakenjos, J.M.,Li, J.Y.,Mishina, Y.,Pan, H.,Qin, X.,Robers, M.B.,Sankaran, B.,Tan, Z.,Tang, S.,Vasquez, Y.M.,Wilkinson, J.,Young, D.W.,Palmer, S.S.,MacKenzie, K.R.,Kim, C.,Matzuk, M.M. Discovery of highly potent and ALK2/ALK1 selective kinase inhibitors using DNA-encoded chemistry technology. Proc.Natl.Acad.Sci.USA, 121:e2413108121-e2413108121, 2024 Cited by PubMed Abstract: 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 Decapentaplegic homolog 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 IC: 0.54 μM] 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. PubMed: 39541346DOI: 10.1073/pnas.2413108121 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.72 Å) |
Structure validation
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