7M5Z

Crystal Structure of the MerTK Kinase Domain in Complex with Inhibitor MIPS15692

Summary for 7M5Z

• Entry DOI: 10.2210/pdb7m5z/pdb
• Descriptor: Tyrosine-protein kinase Mer, 2-(butylamino)-N-[1-(3-fluoropropyl)piperidin-4-yl]-4-{[(1r,4r)-4-hydroxycyclohexyl]amino}pyrimidine-5-carboxamide (3 entities in total)
• Functional Keywords: kinase, signaling protein-inhibitor complex, signaling protein/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 72904.16

Authors

Hermans, S.J.,Hancock, N.C.,Baell, J.B.,Parker, M.W. (deposition date: 2021-03-25, release date: 2021-10-06, Last modification date: 2023-10-18)

Primary citation

Wong, S.W.,Vivash, L.,Mudududdla, R.,Nguyen, N.,Hermans, S.J.,Shackleford, D.M.,Field, J.,Xue, L.,Aprico, A.,Hancock, N.C.,Haskali, M.,Stashko, M.A.,Frye, S.V.,Wang, X.,Binder, M.D.,Ackermann, U.,Parker, M.W.,Kilpatrick, T.J.,Baell, J.B.
Development of [ 18 F]MIPS15692, a radiotracer with in vitro proof-of-concept for the imaging of MER tyrosine kinase (MERTK) in neuroinflammatory disease.
Eur.J.Med.Chem., 226:113822-113822, 2021

PubMed Abstract: MER tyrosine kinase (MERTK) upregulation is associated with M2 polarization of microglia, which plays a vital role in neuroregeneration following damage induced by neuroinflammatory diseases such as multiple sclerosis (MS). Therefore, a radiotracer specific for MERTK could be of great utility in the clinical management of MS, for the detection and differentiation of neuroregenerative and neurodegenerative processes. This study aimed to develop an [F] ligand with high affinity and selectivity for MERTK as a potential positron emission tomography (PET) radiotracer. MIPS15691 and MIPS15692 were synthesized and kinase assays were utilized to determine potency and selectivity for MERTK. Both compounds were shown to be potent against MERTK, with respective IC values of 4.6 nM and 4.0 nM, and were also MERTK-selective. Plasma and brain pharmacokinetics were measured in mice and led to selection of MIPS15692 over MIPS15691. X-ray crystallography was used to visualize how MIPS15692 is recognized by the enzyme. [F]MIPS15692 was synthesized using an automated iPHASE FlexLab module, with a molar activity (A) of 49 ± 26 GBq/μmol. The radiochemical purity of [F]MIPS15692 was >99% and the decay-corrected radiochemical yields (RCYs) were determined as 2.45 ± 0.85%. Brain MERTK protein density was measured by a saturation binding assay in the brain slices of a cuprizone mouse model of MS. High levels of specific binding of [F]MIPS15692 to MERTK were found, especially in the corpus callosum/hippocampus (CC/HC). The in vivo PET imaging study of [F]MIPS15692 suggested that its neuroPK is sub-optimal for clinical use. Current efforts are underway to optimize the neuroPK of our next generation PET radiotracers for maximal in vivo utility.

PubMed: 34563964
DOI: 10.1016/j.ejmech.2021.113822

Experimental method

X-RAY DIFFRACTION (3.06 Å)