Discovery of an SSTR2-Targeting Maytansinoid Conjugate (PEN-221) with Potent Activity in Vitro and in Vivo

• Published in: Journal of medicinal chemistry Vol. 62; no. 5; pp. 2708 - 2719
• Main Authors: White, Brian H, Whalen, Kerry, Kriksciukaite, Kristina, Alargova, Rossitza, Au Yeung, Tsun, Bazinet, Patrick, Brockman, Adam, DuPont, Michelle, Oller, Haley, Lemelin, Charles-Andre, Lim Soo, Patrick, Moreau, Benoît, Perino, Samantha, Quinn, James M, Sharma, Gitanjali, Shinde, Rajesh, Sweryda-Krawiec, Beata, Wooster, Richard, Bilodeau, Mark T
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14-03-2019
• Subjects: Animals; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacokinetics; Antineoplastic Agents, Phytogenic - pharmacology; Cell Line; CHO Cells; Cricetulus; Dogs; Drug Discovery; Humans; Immunoconjugates - chemistry; Immunoconjugates - pharmacology; Maytansine - chemistry; Maytansine - pharmacokinetics; Maytansine - pharmacology; Mice; Receptors, Somatostatin - drug effects; Receptors, Somatostatin - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b02036

Somatostatin receptor 2 (SSTR2) is frequently overexpressed on several types of solid tumors, including neuroendocrine tumors and small-cell lung cancer. Peptide agonists of SSTR2 are rapidly internalized upon binding to the receptor and linking a toxic payload to an SSTR2 agonist is a potential method to kill SSTR2-expressing tumor cells. Herein, we describe our efforts towards an efficacious SSTR2-targeting cytotoxic conjugate; examination of different SSTR2-targeting ligands, conjugation sites, and payloads led to the discovery of 22 (PEN-221), a conjugate consisting of microtubule-targeting agent DM1 linked to the C-terminal side chain of Tyr3–octreotate. PEN-221 demonstrates in vitro activity which is both potent (IC50 = 10 nM) and receptor-dependent (IC50 shifts 90-fold upon receptor blockade). PEN-221 targets high levels of DM1 to SSTR2-expressing xenograft tumors, which has led to tumor regressions in several SSTR2-expressing xenograft mouse models. The safety and efficacy of PEN-221 is currently under evaluation in human clinical trials.