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

Abstract

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.

• Authors: Brian H White, Kerry Whalen, Kristina Kriksciukaite, Rossitza Alargova, Tsun Au Yeung, Patrick Bazinet, Adam Brockman, Michelle DuPont, Haley Oller, Charles-Andre Lemelin, Patrick Lim Soo, Benoît Moreau, Samantha Perino, James M Quinn, Gitanjali Sharma, Rajesh Shinde, Beata Sweryda-Krawiec, Richard Wooster, Mark T Bilodeau
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 62 Issue 5 Pg. 2708-2719 (03 14 2019) ISSN: 1520-4804 [Electronic] United States
• PMID: 30735385 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents, Phytogenic
• Immunoconjugates
• Receptors, Somatostatin
• Maytansine
• somatostatin receptor 2

Topics

• Animals
• Antineoplastic Agents, Phytogenic (chemistry, pharmacokinetics, pharmacology)
• CHO Cells
• Cell Line
• Cricetulus
• Dogs
• Drug Discovery
• Humans
• Immunoconjugates (chemistry, pharmacology)
• Maytansine (chemistry, pharmacokinetics, pharmacology)
• Mice
• Receptors, Somatostatin (drug effects, metabolism)
• Xenograft Model Antitumor Assays