2XIX

Protein kinase Pim-1 in complex with fragment-1 from crystallographic fragment screen

Summary for 2XIX

• Entry DOI: 10.2210/pdb2xix/pdb
• Related: 1XQZ 1XR1 1XWS 1YHS 1YI3 1YI4 1YWV 1YXS 1YXT 1YXU 1YXV 1YXX 2BIK 2BIL 2BZH 2BZI 2BZJ 2BZK 2C3I 2J2I 2XIY 2XIZ 2XJ0 2XJ1 2XJ2
• Descriptor: PROTO-ONCOGENE SERINE/THREONINE-PROTEIN KINASE PIM-1, 3,5-DIAMINO-1H-[1,2,4]TRIAZOLE (3 entities in total)
• Functional Keywords: atp-binding, phosphorylation, transferase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309
• Total number of polymer chains: 1
• Total formula weight: 34568.01

Authors

Schulz, M.N.,Fanghanel, J.,Schafer, M.,Badock, V.,Briem, H.,Boemer, U.,Nguyen, D.,Husemann, M.,Hillig, R.C. (deposition date: 2010-07-01, release date: 2011-02-23, Last modification date: 2024-10-16)

Primary citation

Schulz, M.N.,Fanghanel, J.,Schafer, M.,Badock, V.,Briem, H.,Boemer, U.,Nguyen, D.,Husemann, M.,Hillig, R.C.
Crystallographic Fragment Screen Identifies Cinnamic Acid Derivatives as Starting Points for Potent Pim-1 Inhibitors
Acta Crystallogr.,Sect.D, 67:156-, 2011

PubMed Abstract: A crystallographic fragment screen was carried out to identify starting points for the development of inhibitors of protein kinase Pim-1, a potential target for tumour therapy. All fragment hits identified via soaking in this study turned out to bind to the unusually hydrophobic pocket at the hinge region. The most potent fragments, two cinnamic acid derivatives (with a best IC(50) of 130 µM), additionally form a well defined hydrogen bond. The balance between hydrophobic and polar interactions makes these molecules good starting points for further optimization. Pim-2 inhibitors from a recently reported high-throughput screening campaign also feature a cinnamic acid moiety. Two of these Pim-2 inhibitors were synthesized, their potencies against Pim-1 were determined and their cocrystal structures were elucidated in order to determine to what degree the binding modes identified by fragment screening are conserved in optimized inhibitors. The structures show that the cinnamic acid moieties indeed adopt the same binding mode. Fragment screening thus correctly identified binding modes which are maintained when fragments are grown into larger and higher affinity inhibitors. The high-throughput screening-derived compound (E)-3-{3-[6-(4-aminocyclohexylamino)-pyrazin-2-yl]phenyl}acrylic acid (compound 1) is the most potent inhibitor of the cinnamic acid series for which the three-dimensional binding mode is known (IC(50) = 17 nM, K(d) = 28 nM). The structure reveals the molecular basis for the large gain in potency between the initial fragment hit and this optimized inhibitor.

PubMed: 21358046
DOI: 10.1107/S0907444910054144

Experimental method

X-RAY DIFFRACTION (2.4 Å)