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

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

  • J Med Chem. 2019 Mar 14;62(5):2708-2719. doi: 10.1021/acs.jmedchem.8b02036.
Brian H White 1,  Kerry Whalen 1,  Kristina Kriksciukaite 1,  Rossitza Alargova 1,  Tsun Au Yeung 1,  Patrick Bazinet 1,  Adam Brockman 1,  Michelle DuPont 1,  Haley Oller 1,  Charles-Andre Lemelin 1,  Patrick Lim Soo 1,  Benoît Moreau 1,  Samantha Perino 1,  James M Quinn 1,  Gitanjali Sharma 1,  Rajesh Shinde 1,  Beata Sweryda-Krawiec 1,  Richard Wooster 1,  Mark T Bilodeau 1
Affiliations

Affiliation

  • 1 Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States.
PMID: 30735385 DOI: 10.1021/acs.jmedchem.8b02036
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.

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