3VS5

Crystal structure of HCK complexed with a pyrrolo-pyrimidine inhibitor 7-(1-methylpiperidin-4-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Summary for 3VS5

• Entry DOI: 10.2210/pdb3vs5/pdb
• Related: 3VRY 3VRZ 3VS0 3VS1 3VS2 3VS3 3VS4 3VS6 3VS7
• Descriptor: Tyrosine-protein kinase HCK, 7-(1-methylpiperidin-4-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, CALCIUM ION, ... (4 entities in total)
• Functional Keywords: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Isoform 1: Lysosome. Isoform 2: Cell membrane; Lipid-anchor. Cytoplasmic vesicle, secretory vesicle: P08631
• Total number of polymer chains: 2
• Total formula weight: 104879.59

Authors

Kuratani, M.,Tomabechi, Y.,Handa, N.,Yokoyama, S. (deposition date: 2012-04-21, release date: 2013-05-01, Last modification date: 2023-12-06)

Primary citation

Saito, Y.,Yuki, H.,Kuratani, M.,Hashizume, Y.,Takagi, S.,Honma, T.,Tanaka, A.,Shirouzu, M.,Mikuni, J.,Handa, N.,Ogahara, I.,Sone, A.,Najima, Y.,Tomabechi, Y.,Wakiyama, M.,Uchida, N.,Tomizawa-Murasawa, M.,Kaneko, A.,Tanaka, S.,Suzuki, N.,Kajita, H.,Aoki, Y.,Ohara, O.,Shultz, L.D.,Fukami, T.,Goto, T.,Taniguchi, S.,Yokoyama, S.,Ishikawa, F.
A Pyrrolo-Pyrimidine Derivative Targets Human Primary AML Stem Cells in Vivo
Sci Transl Med, 5:181ra52-181ra52, 2013

PubMed Abstract: Leukemia stem cells (LSCs) that survive conventional chemotherapy are thought to contribute to disease relapse, leading to poor long-term outcomes for patients with acute myeloid leukemia (AML). We previously identified a Src-family kinase (SFK) member, hematopoietic cell kinase (HCK), as a molecular target that is highly differentially expressed in human primary LSCs compared with human normal hematopoietic stem cells (HSCs). We performed a large-scale chemical library screen that integrated a high-throughput enzyme inhibition assay, in silico binding prediction, and crystal structure determination and found a candidate HCK inhibitor, RK-20449, a pyrrolo-pyrimidine derivative with an enzymatic IC50 (half maximal inhibitory concentration) in the subnanomolar range. A crystal structure revealed that RK-20449 bound the activation pocket of HCK. In vivo administration of RK-20449 to nonobese diabetic (NOD)/severe combined immunodeficient (SCID)/IL2rg(null) mice engrafted with highly aggressive therapy-resistant AML significantly reduced human LSC and non-stem AML burden. By eliminating chemotherapy-resistant LSCs, RK-20449 may help to prevent relapse and lead to improved patient outcomes in AML.

PubMed: 23596204
DOI: 10.1126/scitranslmed.3004387

Experimental method

X-RAY DIFFRACTION (2.851 Å)