A DNA-encoded chemical library based on chiral 4-amino-proline enables stereospecific isozyme-selective protein recognition

Discovery of Glutamate Carboxypeptidase III Ligands to Compete the Uptake of [177Lu]Lu-PSMA-617 in Healthy Organs

“…With the aim of identifying GCPIII-selective ligands, a prolinebased DNA-encoded chemical library was screened in parallel against human recombinant GCPIII and PSMA (GCPII). 35 Several library members incorporating building block B795 were found as selectively enriched after screening against GCPIII but not PSMA. The highest enrichment factor for GCPIII (EF GCPIII = 253) was observed for compound A283/ B795, which was 10-fold higher in comparison to the enrichment obtained after selections against PSMA (EF PSMA = 24) (Figure 1A−C).…”

“…35−37 For example, we reported carbonic anhydrase IX and SARS-CoV-2 nonstructural protein 14 ligands with >1000-fold stereoselectivity. 35 To investigate the linker impact, the (2S, 4R) isomer of the hit was connected to fluorescein isothiocyanate (FITC) via a C 6 (compound 1), a PEG 2 (compound 2), or a lysine linker (compound 3) (Figure 2B). All compounds bound to GCPIII with a dissociation constant in the nanomolar concentration range as observed by FP measurements (Figure 2A).…”

“…With the aim of identifying GCPIII-selective ligands, a proline-based DNA-encoded chemical library was screened in parallel against human recombinant GCPIII and PSMA (GCPII) . Several library members incorporating building block B795 were found as selectively enriched after screening against GCPIII but not PSMA.…”

DNA-encoded chemical libraries enable the discovery of potent PSMA-ligands with substantially reduced affinity towards the GCPIII anti-target

“…This antigen is abundantly expressed in the salivary glands and kidneys (by immunouorescence studies), 31 and this molecular event may be responsible for the accumulation of biocidal radiation in healthy structures. Despite documented efforts to identify ligands specic to PSMA over GCPIII, 33,34 PSMA-targeted RLTs which show high tumor-to-salivary gland and tumor-to-kidney ratios have not yet been reported.…”

sp3‐Rich Heterocycle Synthesis on DNA: Application to DNA‐Encoded Library Production

“…[13a] Schreiber has also reported cycloaddition reactions to build sp 3 -rich bicyclic molecules using strained allenes, [14] and Molander has shown hydroalkylation of olefin functionalized DNA. [11b] Schreiber and Clemmons, [15] and Favalli and Bassi [16] have each additionally shown the benefits of scaffold-based stereochemical diversity made possible by building DELs from pre-formed chiral pyrrolidine cores.…”