Crystal structure of pim1 kinase in complex with a pyrido[4,3-d]pyrimidine derivative suggests a unique binding mode.
Human Pim1 kinase is a serine/threonine protein kinase that plays important biological roles in cell survival, apoptosis, proliferation, and differentiation. Moreover, Pim1 is up-regulated in various hematopoietic malignancies and solid tumors. Thus, Pim1 is an attractive target for cancer therapeut...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3729456?pdf=render |
| _version_ | 1818313957453070336 |
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| author | Sang Jae Lee Byeong-Gu Han Jea-Won Cho Jang-Sik Choi Jaekyoo Lee Ho-Juhn Song Jong Sung Koh Byung Il Lee |
| author_facet | Sang Jae Lee Byeong-Gu Han Jea-Won Cho Jang-Sik Choi Jaekyoo Lee Ho-Juhn Song Jong Sung Koh Byung Il Lee |
| author_sort | Sang Jae Lee |
| collection | DOAJ |
| description | Human Pim1 kinase is a serine/threonine protein kinase that plays important biological roles in cell survival, apoptosis, proliferation, and differentiation. Moreover, Pim1 is up-regulated in various hematopoietic malignancies and solid tumors. Thus, Pim1 is an attractive target for cancer therapeutics, and there has been growing interest in developing small molecule inhibitors for Pim1. Here, we describe the crystal structure of Pim1 in complex with a newly developed pyrido[4,3-d]pyrimidine-derivative inhibitor (SKI-O-068). Our inhibitor exhibits a half maximum inhibitory concentration (IC50) of 123 (±14) nM and has an unusual binding mode in complex with Pim1 kinase. The interactions between SKI-O-068 and the Pim1 active site pocket residue are different from those of other scaffold inhibitor-bound structures. The binding mode analysis suggests that the SKI-O-068 inhibitor can be improved by introducing functional groups that facilitate direct interaction with Lys67, which aid in the design of an optimized inhibitor. |
| first_indexed | 2024-12-13T08:42:00Z |
| format | Article |
| id | doaj.art-6a04247e61ce4666b5ac4b22307d5b59 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T08:42:00Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-6a04247e61ce4666b5ac4b22307d5b592022-12-21T23:53:30ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0187e7035810.1371/journal.pone.0070358Crystal structure of pim1 kinase in complex with a pyrido[4,3-d]pyrimidine derivative suggests a unique binding mode.Sang Jae LeeByeong-Gu HanJea-Won ChoJang-Sik ChoiJaekyoo LeeHo-Juhn SongJong Sung KohByung Il LeeHuman Pim1 kinase is a serine/threonine protein kinase that plays important biological roles in cell survival, apoptosis, proliferation, and differentiation. Moreover, Pim1 is up-regulated in various hematopoietic malignancies and solid tumors. Thus, Pim1 is an attractive target for cancer therapeutics, and there has been growing interest in developing small molecule inhibitors for Pim1. Here, we describe the crystal structure of Pim1 in complex with a newly developed pyrido[4,3-d]pyrimidine-derivative inhibitor (SKI-O-068). Our inhibitor exhibits a half maximum inhibitory concentration (IC50) of 123 (±14) nM and has an unusual binding mode in complex with Pim1 kinase. The interactions between SKI-O-068 and the Pim1 active site pocket residue are different from those of other scaffold inhibitor-bound structures. The binding mode analysis suggests that the SKI-O-068 inhibitor can be improved by introducing functional groups that facilitate direct interaction with Lys67, which aid in the design of an optimized inhibitor.http://europepmc.org/articles/PMC3729456?pdf=render |
| spellingShingle | Sang Jae Lee Byeong-Gu Han Jea-Won Cho Jang-Sik Choi Jaekyoo Lee Ho-Juhn Song Jong Sung Koh Byung Il Lee Crystal structure of pim1 kinase in complex with a pyrido[4,3-d]pyrimidine derivative suggests a unique binding mode. PLoS ONE |
| title | Crystal structure of pim1 kinase in complex with a pyrido[4,3-d]pyrimidine derivative suggests a unique binding mode. |
| title_full | Crystal structure of pim1 kinase in complex with a pyrido[4,3-d]pyrimidine derivative suggests a unique binding mode. |
| title_fullStr | Crystal structure of pim1 kinase in complex with a pyrido[4,3-d]pyrimidine derivative suggests a unique binding mode. |
| title_full_unstemmed | Crystal structure of pim1 kinase in complex with a pyrido[4,3-d]pyrimidine derivative suggests a unique binding mode. |
| title_short | Crystal structure of pim1 kinase in complex with a pyrido[4,3-d]pyrimidine derivative suggests a unique binding mode. |
| title_sort | crystal structure of pim1 kinase in complex with a pyrido 4 3 d pyrimidine derivative suggests a unique binding mode |
| url | http://europepmc.org/articles/PMC3729456?pdf=render |
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