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

Autor: White BH; Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States., Whalen K; Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States., Kriksciukaite K; Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States., Alargova R; Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States., Au Yeung T; Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States., Bazinet P; Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States., Brockman A; Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States., DuPont M; Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States., Oller H; Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States., Lemelin CA; Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States., Lim Soo P; Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States., Moreau B; Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States., Perino S; Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States., Quinn JM; Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States., Sharma G; Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States., Shinde R; Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States., Sweryda-Krawiec B; Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States., Wooster R; Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States., Bilodeau MT; Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2019 Mar 14; Vol. 62 (5), pp. 2708-2719. Date of Electronic Publication: 2019 Feb 28.
DOI: 10.1021/acs.jmedchem.8b02036
Abstrakt: 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 Tyr 3 -octreotate. PEN-221 demonstrates in vitro activity which is both potent (IC 50 = 10 nM) and receptor-dependent (IC 50 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.
Databáze: MEDLINE
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