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In recent years, a number of drugs targeting the prostate-specific membrane antigen (PSMA) have become important tools in the diagnosis and treatment of prostate cancer. In the present work, we report on the synthesis and preclinical evaluation of a series of 18F-labeled PSMA ligands for diagnostic application based on the theragnostic ligand PSMA-617. By applying modifications to the linker structure, insight into the structure-activity relationship could be gained, highlighting the importance of hydrophilicity and stereoselectivity on interaction with PSMA and hence the biodistribution. Selected compounds were co-crystallized with the PSMA protein and analyzed by X-rays with mixed results. Among these, PSMA-1007 (compound 5) showed the best interaction with the PSMA protein. The respective radiotracer [18F]PSMA-1007 was translated into the clinic and is, in the meantime, subject of advanced clinical trials.

Bioorganic & medicinal chemistry 27(2), 255 - 264 (2019). doi:10.1016/j.bmc.2018.11.022, A series of carbamate-based inhibitors of glutamate carboxypeptidase II (GCPII) were designed and synthesizedusing ZJ-43, N-[[[(1S)-1-carboxy-3-methylbutyl]amino]carbonyl]-L-glutamic acid, as a molecular template inorder to better understand the impact of replacing one of the two nitrogen atoms in the urea-based GCPIIinhibitor with an oxygen atom. Compound 7 containing a C-terminal 2-oxypentanedioic acid was more potentthan compound 5 containing a C-terminal glutamic acid (2-aminopentanedioic acid) despite GCPII’s preferencefor peptides containing an N-terminal glutamate as substrates. Subsequent crystallographic analysis revealedthat ZJ-43 and its two carbamate analogs 5 and 7 with the same (S,S)-stereochemical configuration adopt anearly identical binding mode while (R,S)-carbamate analog 8 containing a D-leucine forms a less extensivehydrogen bonding network. QM and QM/MM calculations have identified no specific interactions in the GCPIIactive site that would distinguish ZJ-43 from compounds 5 and 7 and attributed the higher potency of ZJ-43 andcompound 7 to the free energy changes associated with the transfer of the ligand from bulk solvent to the proteinactive site as a result of the lower ligand strain energy and solvation/desolvation energy. Our findings underscorea broader range of factors that need to be taken into account in predicting ligand-protein binding affinity.These insights should be of particular importance in future efforts to design and develop GCPII inhibitors foroptimal inhibitory potency., Published by Elsevier, Amsterdam [u.a.]

Prostate-specific membrane antigen (PSMA) is an excellent biomarker for the early diagnosis of prostate cancer progression and metastasis. The most promising PSMA-targeted agents in the clinical phase are based on the Lys-urea-Glu motif, in which Lys and Glu are α-(l)-amino acids. In this study, we aimed to determine the effect of β- and γ-amino acids in the S1 pocket on the binding affinity for PSMA. We synthesized and evaluated the β- and γ-amino acid analogues with (S)- or (R)-configuration with keeping α-(l)-Glu as the S1'-binding pharmacophore. The structure-activity relationship studies identified that compound 13c, a β-amino acid analogue with (R)-configuration, exhibited the most potent PSMA inhibitory activity with an IC50 value of 3.97 nM. The X-ray crystal structure of PSMA in complex with 13c provided a mechanistic basis for the stereochemical preference of PSMA, which can guide the development of future PSMA inhibitors.

[Image: see text] Tubastatin A, a tetrahydro-γ-carboline-capped selective HDAC6 inhibitor (HDAC6i), was rationally designed 10 years ago, and has become the best investigated HDAC6i to date. It shows efficacy in various neurological disease animal models, as HDAC6 plays a crucial regulatory role in axonal transport deficits, protein aggregation, as well as oxidative stress. In this work, we provide new insights into this HDAC6i by investigating the molecular basis of its interactions with HDAC6 through X-ray crystallography, determining its functional capability to elevate the levels of acetylated α-tubulin in vitro and in vivo, correlating PK/PD profiles to determine effective doses in plasma and brain, and finally assessing its therapeutic potential toward psychiatric diseases through use of the SmartCube screening platform.

[Image: see text] The design and synthesis of prostate specific membrane antigen (PSMA) ligands derived from 2-aminoadipic acid, a building block that has not previously been used to construct PSMA ligands, are reported. The effects of both the linker length and of an N-substituent of our PSMA ligands were probed, and X-ray structures of five of these ligands bound to PSMA were obtained. Among the ligands disclosed herein, 13b showed the highest inhibitory activity for PSMA. As ligand 13b can readily be radiolabeled since its fluorine atom is adjacent to the nitrogen atom of its pyridine ring, the use of this and related compounds as theranostics can be pursued.