Discovery of potent Abelson kinase inhibitors from the scaffold of pyrano[2,3-d]pyrimidin-7-one
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AbstractTyrosine kinases regulate cell proliferation, survival, invasion and angiogenesis during tumor initiation and progression. The Abelson (ABL) family of protein kinases comprises ABL1 and ABL2, which link diverse extracellular stimuli to signaling pathways that control cell growth, survival, invasion, adhesion and migration. Inhibition of ABLs has been implied in many type of hematopoietic malignancies and solid tumors. The compound PD173955 is a potent ABL kinase inhibitor. It was developed from the scaffold pyrido[2,3-d]pyrimidin-7-one by Parke-Davis (Pfizer). To discover novel ABL inhibitors, we investigated the scaffold pyrano[2,3-d]pyrimidin-7-one, which is structurally analogous to pyrido[2,3-d]pyrimidin-7-one. This novel scaffold has not been extensively studied in synthetic chemistry and pharmacology. The compound LDK1504 generated from this scaffold is a close analog of PD173955. It was synthesized as a prototypical compound from the pyrano[2,3-d]pyrimidin-7-one scaffold. In the enzymatic assays, LDK1504 was demonstrated with an inhibitory activity comparable to PD173955 for ABL1 kinase. It can inhibit the ABL1 kinase with an IC50 of 18.7 nM. Further optimization leads to the identification of LDK1512 (Kd = 0.38 nM; IC50 = 1.27 nM) against ABL1. The preparation of this class of compounds was achieved through a facile synthesis of 6-bromo-2-(methylthio)-7H-pyrano[2,3-d]pyrimidin-7-one followed by Suzuki coupling reaction and derivatization of the C-2 position of the pyrimidine ring. In this presentation, our synthesis, preliminary SAR of this class of compounds, and kinase selectivity profiling will be discussed.Citation Format: Zhixing Wu, Boqiao Fu, Changjiang Qiao, Ashila Nagaraju, Dai Lu. Discovery of potent Abelson kinase inhibitors from the scaffold of pyrano[2,3-d]pyrimidin-7-one [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1661.
