Conjugating Small Molecule Drugs

Published on 19/09/2023

You want to attach your small molecule to a certain carrier? Let’s analyze the functional groups present and discuss Linkerology® possibilities for permanent or trigger-inducible, tracelessly-cleavable linkage.

Conjugating highly potent small molecule drugs to vastly target specific biomolecules, such as antibodies, has become a sophisticated approach to avoid the disadvantages of both players, namely off-target side-effects, and low specificity. The field of antibody-drug-conjugates (ADCs) is constantly growing being valued at around USD 8 billion in 2022 and predicted around USD 36 billion by 2029.

Antibodies with improved binding specificity, enhanced stability, and reduced immunogenicity are being developed, as well as improved linker technologies, allowing for the creation of more effective ADCs. Besides, currently, most of the approved ADCs are used in the treatment of cancer, but there are other diseases to be treated keeping the field promising.

To construct an antibody-drug conjugate, a linker needs to be incorporated between antibody and payload, releasing the native drug after internalization. In the following, we selected a few top selling drugs and demonstrate, how they can be decorated with self-immolative linkers allowing trigger-induced disassembly of the final construct into its constituent fragments.

We focus on the presence of different functional groups within the drug molecules to showcase the versatility of Linkerology®. Of course, the linker-drug conjugate can be loaded onto different carriers, also inorganics (e.g. metals, metal oxides, silicates) and polymers (e.g. latex, polyethylene, polytetrafluoroethylene) and is not limited to biomolecules like antibodies.

Functional group	Secondary amine
Brand names	Cymbalta, Drizalma Sprinkle, Irenka
Generic name	Duloxetine
Route of administration	Oral
Drug class	Serotonin-norepinephrine reuptake inhibitor
Sales in 2022	$328 Million
Indications	Major depressive disorder, generalized anxiety disorder, neuropathic pain, chronic musculoskeletal pain, fibromyalgia
CAS #	116539-59-4

Duloxetine is small molecule drug acting as serotonin–norepinephrine reuptake inhibitor (SNRI). Its secondary amine function can be conjugated to a valine-citrulline-PAB linker which releases the drug molecule in a self-immolative manner, once the citrulline amide bond is being hydrolyzed and cleaved by proteases such as cathepsin B.

Conjugation of Duloxetine via its secondary amine towards an peptidic Val-Cit-PAB linker and protease-induced disassembly.

Functional group	Tertiary amine
Brand names	Vraylar, Reagila
Generic name	Cariprazine
Route of administration	Oral
Drug class	Atypical antipsychotic
Sales in 2022	$ 2.038 Billion
Indications	Schizophrenia, bipolar mania, bipolar depression, major depressive disorder
CAS #	839712-12-8

Cariprazine is a small molecule drug bearing a tertiary amine function. It is an atypical antipsychotic drug. Alkylation with a valine-alanine-PAB linker will yield a quaternary ammonium function which releases the drug molecule in a self-immolative manner, once the alanine amide bond is being hydrolyzed and cleaved by proteases such as cathepsin B.

Conjugation of Cariprazine via its tertiary amine towards an peptidic Val-Ala-PAB linker and protease-induced disassembly.

Functional group	Carboxylic acid
Brand names	Vyndaqel, Vyndamax
Generic name	Tafamidis
Route of administration	Oral
Drug class	Pharmacological chaperone
Sales in 2022	$2.447 Billion
Indications	Transthyretin amyloidosis, familial amyloid cardiomyopathy, familial amyloid polyneuropathy, transthyretin amyloidosis
CAS #	594839-88-0

Tafamidis is a small molecule drug bearing a carboxylic acid as the only chemically reactive group. It is a pharmacological chaperone. Esters with p-mercaptobenzyl linkers can be formed and will fragmentize once the adjacent formed disulfide bond will be cleaved in reductive environment, e.g. by glutathione in the cytosol.

Conjugation of Tafamidis via its carboxylic acid forming a p-mercaptobenzyl ester and reductive cleavage of the adjacent disulfide.

→ For more details on the conjugation of small molecule drugs, click here!

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References:

Introduction to Antibody-Drug Conjugates; M. C. Pettinato, Antibodies (Basel) 2021; 10(4): 42. https://doi.org/10.3390/antib10040042

https://njardarson.lab.arizona.edu/

A Graphical Journey of Innovative Organic Architectures That Have Improved Our Lives; N. A. McGrath, M. Brichacek, J. T. Njardarson; J. Chem. Educ. 2010; 87(12): 1348-1349. https://doi.org/10.1021/ed1003806

https://www.grandviewresearch.com/industry-analysis/antibody-drug-conjugates-market

Linker Technologies for Antibody–Drug Conjugates; B. Nolting; Antibody-Drug Conjugates L. Ducry 2013; 1045: 71-100. https://doi.org/10.1007/978-1-62703-541-5_5