8XB1

Crystal structure of FLT3 in complex with a Pyrazinamide Macrocycle derivative

Summary for 8XB1

• Entry DOI: 10.2210/pdb8xb1/pdb
• Descriptor: Receptor-type tyrosine-protein kinase FLT3, 3^3-ethyl-5^4-morpholino-6,9-dioxa-2,4-diaza-3(2,6)-pyrazina-1(4,1)-piperidina-5(1,3)-benzenacycloundecaphane-3^5-carboxamide (2 entities in total)
• Functional Keywords: inhibitor, kinase, macrocycle derivative, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens
• Total number of polymer chains: 1
• Total formula weight: 40439.07

Authors

Guo, M.,Chen, Y. (deposition date: 2023-12-05, release date: 2024-12-11)

Primary citation

Zheng, X.,Chen, Z.,Guo, M.,Liang, H.,Song, X.,Liu, Y.,Liao, Z.,Zhang, Y.,Guo, J.,Zhou, Y.,Zhang, Z.M.,Tu, Z.,Zhang, Y.,Chen, Y.,Zhang, Z.,Lu, X.
Structure-Based Optimization of Pyrazinamide-Containing Macrocyclic Derivatives as Fms-like Tyrosine Kinase 3 (FLT3) Inhibitors to Overcome Clinical Mutations.
Acs Pharmacol Transl Sci, 7:1485-1506, 2024

PubMed Abstract: Secondary mutations in Fms-like tyrosine kinase 3-tyrosine kinase domain (FLT3-TKD) (e.g., D835Y and F691L) have become a major on-target resistance mechanism of FLT3 inhibitors, which present a significant clinical challenge. To date, no effective drugs have been approved to simultaneously overcome clinical resistance caused by these two mutants. Thus, a series of pyrazinamide macrocyclic compounds were first designed and evaluated to overcome the secondary mutations of FLT3. The representative exhibited potent inhibitory activities against FLT3 and FLT3 with IC values of 1.5 and 9.7 nM, respectively. also strongly suppressed the proliferation against Ba/F3 cells transfected with FLT3-ITD, FLT3-ITD-D835Y, FLT3-ITD-F691L, FLT3-ITD-D835Y-F691L, and MV4-11 acute myeloid leukemia (AML) cell lines with IC values of 12.2, 10.5, 24.6, 16.9, and 6.8 nM, respectively. Furthermore, demonstrated ideal anticancer efficacy in a Ba/F3-FLT3-ITD-D835Y xenograft model. The results suggested that can serve as a promising macrocycle-based FLT3 inhibitor for the treatment of AML.

PubMed: 38751627
DOI: 10.1021/acsptsci.4c00071

Experimental method

X-RAY DIFFRACTION (2.85 Å)