Modular Smart Molecules for PSMA-Targeted Chemotherapy

Abstract

New targeted chemotherapeutics are urgently needed to minimize off-target toxicity and reduce the high mortality rate associated with metastatic prostate cancer (PCa). We report on the modular synthesis, pharmacokinetics, and efficacy of two small-molecule drug-conjugates (SMDCs) targeted to prostate-specific membrane antigen (PSMA) incorporating either: (1) a cathepsin-B cleavable valine-citrulline, or (2) an acid-responsive phosphoramidate linker. Key to the selectivity of these conjugates is CTT1298, a nanomolar affinity ligand that binds irreversibly to PSMA and has been shown to rapidly internalize payloads into PSMA-expressing PCa cells. Other crucial components in the design of the conjugates include: (1) MMAE, a known potent cytotoxic payload, and (2) an albumin-binder, proven to improve residence time of drug conjugates. At a dose of 0.8 mg/kg (~250 nmol/kg), both SMDCs showed significant efficacy in a PSMA(+) PC3-PIP mouse model of human PCa compared to controls, without inducing systemic toxicity. Though localization of the SMDCs was observed in tissues apart from the tumor, release of MMAE was observed predominantly in tumor tissue, at levels 2-3 orders of magnitude higher than non-target tissues. Furthermore, SMDC 2, which incorporated a novel pH-responsive phosporamidate linker, demonstrated improved efficacy over SMDC 1 that has a valine-citrulline linker, with a 100% survival over 90 days and 4 out of 8 mice showing complete tumor growth inhibition after 6 weekly doses of 0.8 mg/kg (244 nmol/kg). Our findings demonstrate the potential of irreversible PSMA inhibitors combined with pH-responsive linkers as a way to specifically deliver chemotherapeutic drugs to PCa tumors with minimal toxicity.

Synthesis and Evaluation of ePSMA-DM1: A New Theranostic Small-Molecule Drug Conjugate (T-SMDC) for Prostate Cancer

“…In this study, we aimed to develop a PSMA-targeting theranostic small-molecule drug conjugate (T-SMDC) for the imaging of and combined therapy for prostate cancer. SMDCs are emerging as a form of targeted chemotherapy, with several promising SMDCs targeting PSMA being reported in the literature [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. However, SMDCs must be carefully designed in order to maximize their therapeutic efficacy.…”

“…If a cleavable bond is present, it releases the cytotoxic agent specifically at the tumor site, to prevent off-target toxicity. Currently, a few SMDCs targeting PSMA have been described in the literature, featuring therapeutic payloads such as MMAE [ 18 , 19 , 20 ], tubulysin [ 21 , 22 ], topoisomerase inhibitors [ 23 ] and taxanes [ 24 , 25 ]. Some of these agents also include a chelator for the complexation of a radionuclide to enable companion diagnostics [ 26 ].…”

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

“…5 Prostate-specic membrane antigen (PSMA) 6 is one of the few examples of tumor-associated antigens which have been validated through nuclear medicine studies for the development of targeted anti-cancer RLTs. 7,8 While the physiological function of PSMA in prostate cells is not yet fully understood, [9][10][11][12] its pronounced upregulation within prostate cancer lesions led to the development of high-affinity monoclonal antibodies and small organic ligands, [13][14][15][16][17][18][19][20] including (2S,2 0 S)-2,2 0 -(carbonyldiimino)dipentanedioic acid (DUPA, IC 50,PSMA = 47 nM). 21 Further chemical elaborations on DUPA prompted the identi-cation of PSMA-11 22 and PSMA-617 23 as lead compounds for diagnostic and therapeutic applications (respectively) with excellent biodistribution proles in tumor-bearing mice 24,25 and patients.…”

Optimizing the enzymatic release of MMAE from isoDGR-based small molecule drug conjugate by incorporation of a GPLG-PABC enzymatically cleavable linker

“…In particular, the compound known as vintafolide (or EC145), in which the folic acid ligand is connected to desacetylvinblastine through a disulfide bond, is in phase III clinical trials (ID: NCT01170650). To follow, prostate specific membrane antigen ( Olatunji et al, 2022 ), somatostatin receptor ( Figueras et al, 2019 ), glucose transporter 1 receptor ( Fu et al, 2020 ) and α V β 3 integrin receptor ( Lerchen et al, 2022 ) ligands have been also efficiently used in SMDCs that are currently in preclinical or clinical development ( Patel et al, 2021 ). Furthermore, two radioactive SMDCs ( Hennrich and Kopka, 2019 ; Hennrich and Eder, 2022 ) were recently approved by FDA and EMA and are now commercially available.…”