8FEC

Structure of J-PKAc chimera complexed with Aplithianine derivative

Summary for 8FEC

• Entry DOI: 10.2210/pdb8fec/pdb
• Related: 8FE2 8FE5
• Descriptor: DnaJ homolog subfamily B member 1,cAMP-dependent protein kinase catalytic subunit alpha, cAMP-dependent protein kinase inhibitor alpha, 6-[(6P)-6-(4-bromo-1-methyl-1H-imidazol-5-yl)-2,3-dihydro-4H-1,4-thiazin-4-yl]-7H-purine, ... (4 entities in total)
• Functional Keywords: protein kinase a, fibrolamellar hepatocellular carcinoma, natural product, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 100313.24

Authors

Du, L.,Wilson, B.A.P.,Li, N.,Martinez Fiesco, J.A.,Dalilian, M.,Wang, D.,Smith, E.A.,Wamiru, A.,Goncharova, E.I.,Zhang, P.,O'Keefe, B.R. (deposition date: 2022-12-06, release date: 2023-10-18, Last modification date: 2024-11-13)

Primary citation

Du, L.,Wilson, B.A.P.,Li, N.,Shah, R.,Dalilian, M.,Wang, D.,Smith, E.A.,Wamiru, A.,Goncharova, E.I.,Zhang, P.,O'Keefe, B.R.
Discovery and Synthesis of a Naturally Derived Protein Kinase Inhibitor that Selectively Inhibits Distinct Classes of Serine/Threonine Kinases.
J.Nat.Prod., 86:2283-2293, 2023

PubMed Abstract: The oncogenic gene fusion results in an active kinase enzyme, J-PKAcα, that has been identified as an attractive antitumor target for fibrolamellar hepatocellular carcinoma (FLHCC). A high-throughput assay was used to identify inhibitors of J-PKAcα catalytic activity by screening the NCI Program for Natural Product Discovery (NPNPD) prefractionated natural product library. Purification of the active agent from a single fraction of an sp. marine tunicate led to the discovery of two unprecedented alkaloids, aplithianines A () and B (). Aplithianine A () showed potent inhibition against J-PKAcα with an IC of ∼1 μM in the primary screening assay. In kinome screening, inhibited wild-type PKA with an IC of 84 nM. Further mechanistic studies including cocrystallization and X-ray diffraction experiments revealed that inhibited PKAcα catalytic activity by competitively binding to the ATP pocket. Human kinome profiling of against a panel of 370 kinases revealed potent inhibition of select serine/threonine kinases in the CLK and PKG families with IC values in the range ∼11-90 nM. An efficient, four-step total synthesis of has been accomplished, enabling further evaluation of aplithianines as biologically relevant kinase inhibitors.

PubMed: 37843072
DOI: 10.1021/acs.jnatprod.3c00394

Experimental method

X-RAY DIFFRACTION (2.7 Å)