Levocabastine Hydrochloride

Glioblastoma, the most severe form of brain tumor and a leading cause of death within a year of diagnosis, is characterized by excessive protein synthesis and folding in the lumen of the endoplasmic reticulum (ER), leading to increased ER stress in the cells of GBM tissues. To mitigate this stress the cancer cells have intelligently adopted a plethora of response mechanisms and Unfolded Protein Response (UPR) is one of those. To bear with this exhaustive situation cells upregulate a strong protein degradation system in form of 26S proteasome and blocking of proteasomal gene synthesis may be a potential therapeutic action against GBM. Proteasomal gene synthesis is exclusively dependent on the transcription factor Nuclear respiratory factor 1 (NRF1) and its activating enzyme DNA damage inducible 1 homolog 2 (DDI2). Here in this study, we performed molecular docking against DDI2 with the 20 FDA-approved drugs and identified Alvimopan and Levocabastine as the top two compounds with the best binding score along with the standard drug Nelfinavir. MD simulation (100 ns) of these protein-ligand docked complexes reveals that the stability and compactness of Alvimopan are high in comparison with Nelfinavir. Our in-silico (Molecular docking and Molecular dynamics simulation) studies pointed out that Alvimopan may be repurposed as a DDI2 inhibitor and can be used as a potential anticancer agent for the treatment of brain tumors.Communicated by Ramaswamy H. Sarma.

Neurotensin receptor 2 (NTS₂) is a well-known mediator of central opioid-independent analgesia. Seminal studies have highlighted NTS₂ overexpression in a variety of tumors including prostate cancer, pancreas adenocarcinoma, and breast cancer. Herein, we describe the first radiometalated neurotensin analogue targeting NTS₂. JMV 7488 (DOTA-(βAla)₂-Lys-Lys-Pro-(D)Trp-Ile-TMSAla-OH) was prepared using solid-phase peptide synthesis, then purified, radiolabeled with ⁶⁸Ga and ¹¹¹In, and investigated in vitro on HT-29 cells and MCF-7 cells, respectively, and in vivo on HT-29 xenografts. [⁶⁸Ga]Ga-JMV 7488 and [¹¹¹In]In-JMV 7488 were quite hydrophilic (logD_7.4 = -3.1 ± 0.2 and -2.7 ± 0.2, respectively, p < 0.0001). Saturation binding studies showed good affinity toward NTS₂ (K _D = 38 ± 17 nM for [⁶⁸Ga]Ga-JMV 7488 on HT-29 and 36 ± 10 nM on MCF-7 cells; K _D = 36 ± 4 nM for [¹¹¹In]In-JMV 7488 on HT-29 and 46 ± 1 nM on MCF-7 cells) and good selectivity (no NTS₁ binding up to 500 nM). On cell-based evaluation, [⁶⁸Ga]Ga-JMV 7488 and [¹¹¹In]In-JMV 7488 showed high and fast NTS₂-mediated internalization of 24 ± 5 and 25 ± 11% at 1 h for [¹¹¹In]In-JMV 7488, respectively, along with low NTS₂-membrane binding (<8%). Efflux was as high as 66 ± 9% at 45 min for [⁶⁸Ga]Ga-JMV 7488 on HT-29 and increased for [¹¹¹In]In-JMV 7488 up to 73 ± 16% on HT-29 and 78 ± 9% on MCF-7 cells at 2 h. Maximum intracellular calcium mobilization of JMV 7488 was 91 ± 11% to that of levocabastine, a known NTS₂ agonist on HT-29 cells demonstrating the agonist behavior of JMV 7488. In nude mice bearing HT-29 xenograft, [⁶⁸Ga]Ga-JMV 7488 showed a moderate but promising significant tumor uptake in biodistribution studies that competes well with other nonmetalated radiotracers targeting NTS₂. Significant uptake was also depicted in lungs. Interestingly, mice prostate also demonstrated [⁶⁸Ga]Ga-JMV 7488 uptake although the mechanism was not NTS₂-mediated.