Click activated protodrugs against cancer increase the therapeutic potential of chemotherapy through local capture and activation

Abstract

The Click Activated Protodrugs Against Cancer (CAPAC) platform uses click chemistry to activate cytotoxic drugs directly at a target site with minimal toxicity, overcoming limitations of conventional chemotherapy and traditional targeted therapies.

Bioorthogonal Chemistry and Its Applications

“…“Click to release” was used by researchers at Shasqi, a California company, and the research group of Maksim Royzen − as a treatment for solid tumors. In their version, a sodium hyaluronate polymer (the green material shown in Figure ) functionalized with tetrazine moieties was injected near the tumor.…”

“…Timeline of developments in and uses of bioorthogonal chemistry. 2000 : Staudinger ligation; 2002 : Copper click chemistry; , 2003 : ABPP; , 2004 : Strain-promoted click chemistry; 2004 : In vivo cell surface glycan imaging; 2006 : BONCAT; 2008 : Tetrazine ligation; , 2010 : FUNCAT; 2012 : Genetic encoding by tetrazine ligation; 2013 : Click to release; 2016 : In situ drug assembly; 2017 : Cancer drug targeting; − 2018 : Click to release; 2021 : Microneedles; 2021 : Click to release. ,, *: from antibody-drug conjugates with systemic tetrazine administration. **: from a systemically administered masked drug with a polymer-bound tetrazine.…”

Recent Development of Prodrugs of Gemcitabine

“…Our group, in collaboration with Shasqi, Inc., recently reported a prodrug of GCB, shown in Figure 7 , whose activation is triggered by bio-orthogonal inverse electron demand Diels-Alder (IEDDA) chemistry between trans -cyclooctene (TCO) and tetrazine (Tz) [ 30 ]. The prodrug, termed GCB-TCO-acid , contains TCO attached to the N4-position of the nucleobase via a carbamate bond.…”

Uncovering the key role of distortion in tetrazine ligations guides the design of bioorthogonal tools with high reactivity and superior stability

“…2,3 Very recently, bioorthogonal chemistry has entered Phase 1 clinical trials, with Tz/TCO-reactions currently being tested in humans, aiming for locally restricted prodrug activation to improve the selectivity of chemotherapeutic treatment of cancer. 9,10 In recent years, a variety of differently substituted tetrazines has been used for bioorthogonal reactions and in vivo chemistry, including bis-alkyl-substituted Tz, [11][12][13][14][15] alkyl-aryl-Tz, [16][17][18][19] monoalkyl-Tz 20 (alkyl-H-Tz) as well as highly reactive bisheteroaryl 21,22 and mono-aryl [23][24][25][26] derivatives (aryl-H-Tz). These applications have motivated and fueled the development of advanced procedures for the synthesis of tetrazine scaffolds.…”