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. 2022 Nov 10;65(21):14337-14347.
doi: 10.1021/acs.jmedchem.2c00065. Epub 2022 Oct 6.

Discovery of BT8009: A Nectin-4 Targeting Bicycle Toxin Conjugate for the Treatment of Cancer

Gemma E Mudd  1 , Heather Scott  1 , Liuhong Chen  1 , Katerine van Rietschoten  1 , Gabriela Ivanova-Berndt  1 , Katarzyna Dzionek  1 , Amy Brown  1 , Sophie Watcham  1 , Lewi White  1 , Peter U Park  2 , Phil Jeffrey  1 , Mike Rigby  1 , Paul Beswick  1
Affiliations

Discovery of BT8009: A Nectin-4 Targeting Bicycle Toxin Conjugate for the Treatment of Cancer

Gemma E Mudd et al. J Med Chem. .

Abstract

Bicycle toxin conjugates (BTCs) are a promising new class of molecules for targeted delivery of toxin payloads into tumors. Herein we describe the discovery of BT8009, a Nectin-4 targeting BTC currently under clinical evaluation. Nectin-4 is overexpressed in multiple tumor types and is a clinically validated target for selective delivery of cytotoxic payloads. A Nectin-4 targeting bicyclic peptide was identified by phage display, which showed highly selective binding for Nectin-4 but suffered from low plasma stability and poor physicochemical properties. Multiparameter chemical optimization involving introduction of non-natural amino acids resulted in a lead Bicycle that demonstrated high affinity for Nectin-4, good stability in biological matrices, and a much-improved physicochemical profile. The optimized Bicycle was conjugated to the cytotoxin Monomethyl auristatin E via a cleavable linker to give the targeted drug conjugate BT8009, which demonstrates potent anticancer activity in in vivo rodent models.

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Conflict of interest statement

The authors declare the following competing financial interest(s): GM, HS, LC, KvR, GIB, KD, AB, SW, PP, PJ, MR, and PB are/were shareholders or option holders in Bicycle Therapeutics Plc, the parent company of BicycleTx Ltd.

Figures

Figure 1
Figure 1
Structures of previously reported BTCs BT1718 and BT5528.
Figure 2
Figure 2
Structure of hit Nectin-4 binding Bicycle 7 and corresponding fluorescein labeled analogue 2. The three cysteines used for cyclization are highlighted in orange; TATA scaffold highlighted in purple.
Figure 3
Figure 3
Structure of Bicycle Toxin Conjugate (BT8009).
Figure 4
Figure 4
Efficacy of BT8009 in a breast adenocarcinoma (MDA-MB-468) CDX model.
See this image and copyright information in PMC

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