A new anti-cancer molecule targets disease-causing proteins

Proteins are important biomolecules, fulfilling tasks in every cell of your body and with a central role in health and disease.

Dr. Harald Weinstabl and Dr. Will Farnaby lead collaboration at Boehringer Ingelheim and the University of Dundee  working on PROTACs, a new class of molecules with the potential to  selectively target and destroy disease-causing proteins.

Drs. Weinstabl and Farnaby's interdisciplinary research team has achieved significant tumor growth inhibition in mice, and this molecule is freely available to other researchers. 

Read their original research: https://doi.org/10.1038/s41467-022-33430-6

Transcript

Speaker 1 0:04

Hello and welcome to ResearchPod . Thanks for listening and joining us today . In this episode we will discuss the collaborative research of a joint team led by Dr Harold Weinstabel and Dr Will Farnaby from Böhringer Ingelheim , rcv in Vienna , austria , and the University of Dundee Centre for Targeted Protein Degradation , or CTPD , in Scotland respectively . The team is part of a larger drug discovery collaboration between Professor Alessio Cciulli , the director of CTPD , and Böhringer Ingelheim that is focused around the identification of molecules to selectively target and destroy disease-causing proteins . Proteins are important biomolecules , fulfilling tasks in every cell of your body and coming in many forms . Some act as building blocks for the tissues of the body . Others , such as hormones , deliver messages between different parts of the body . Some proteins work as enzymes , speeding up many physiological processes that would not be feasible in their absence . Those enzymes work within a complex network , depending on other proteins and biomolecules , to control many metabolic processes and take a central role in health and disease . Enzymes convert smaller molecules or substrates into useful products . The enzyme-substrate interaction takes place within the enzyme's active site , that is to say , a cavity or a fold buried within the complex 3D structure of the enzyme , with a shape and electrical charge complementary to those of the substrate . Some reactions can be disrupted by small molecules known as enzyme inhibitors . Why do so many researchers look at enzymes as drug targets to treat disease ? Simply because the interaction between enzymes and their substrates can sometimes become dysfunctional and lead to many health conditions , which include cancer , diabetes and an array of cardiovascular , inflammatory and autoimmune diseases .

Speaker 1 2:12

Scientists have long used the action of enzyme inhibitors as a pharmacological tool to target and halt disease-causing enzyme reactions . Unfortunately , for some types of cancer and many other diseases , enzyme inhibitors either lack efficacy , resulting in resistance to treatment , or fail to selectively bind to their target protein , causing poor tolerability and toxicity issues . The team around Drs Veinshtarbal and Farnaby have demonstrated a solution for the many diseases that do not respond to the action of classic enzyme inhibitors . The scientists explain that a promising class of molecules discovered around 20 years ago are capable of targeting disease-causing proteins and flagging them for destruction by the body . These molecules are known as protax , an acronym that stands for proteolysis targeting chimeras . To achieve their pharmacological action , protax bind to two proteins at the same time , facilitating their physical proximity . The first is the target protein , while the second is known by the name of E3 ligase . The proximity of the two proteins causes another molecule ubiquitin to bind to the target protein . Ubiquitin acts as a tag which instructs the proteasome , a system of molecules responsible for the controlled disassembly of proteins to degrade the target protein . Protax are both selective and defective in the elimination of their targets and offer hope that they could pose a solution to therapeutic resistance for hard-to-treat diseases like cancer . One challenge to the use of protax , however , is the scarcity of orally-available options among the degraded molecules designed to date . Orally-bioavailable drugs offer several advantages over drugs that are injected intravenously , including higher patient acceptance , easier and cost-effective large-scale manufacturing and the possibility of self-administration in non-stereoil conditions . The team has investigated the bioavailability and the in vivo efficacy of a selective and orally-available protax that recruits a specific type of E3 ligase known as von Hippel Lindau E3 or VHL , for simplicity . The team published a study in the journal Nature Communications in 2022 demonstrating the remarkable selectivity of an orally available VHL recruiting protac known as ACBI2 . <div

Speaker 1 6:09

To achieve optimal oral bioavailability and efficacy for their lead compound ACBI2 , which selectively targets SMARCA2 over SMARCA4 , the researchers studied the high-resolution crystal structure of several small molecules , selecting those that could bind effectively and selectively to the SMARCA2 target protein , while retaining the water solubility and absorption characteristics required for the oral route of administration .

Speaker 1 6:37

Once the candidate molecule with optimal structure for the SMARCA2 binder was identified , it was further modified with the addition of small carbon-containing units to enhance the SMARCA2 binding and degrading capability of ACBI2 . The interdisciplinary research team conducted experiments in human whole blood and several cell culture samples , demonstrating that ACBI2 was responsible for the preferential degradation of SMARCA2 of at least 30-fold over SMARCA4 . To assess the in vivo efficacy of the treatment , the researchers tested the SMARCA2 degradation in tumour-bearing mice that were treated with orally-administered ACBI2 . This resulted in a significant inhibition of tumour growth and correlated to a dramatic reduction in the levels of SMARCA2 . The treatment was also well tolerated by the mice , suggesting low toxicity .

Speaker 1 7:32

Taken together , these data led the team to conclude that the orally bioavailable VHL-recruiting-degrader ACBI2 is capable of SMARCA2 dependence , synthetic lethality towards SMARCA4 deficient cancer cells , and that the anti-cancer properties of the compound , either alone or in combination with other drugs , warrant further investigation . Phanabian-veinstein-bel hoped that other researchers and drug developers can benefit from the study To help the scientific community design other potent and selective oral route orally-bioavailable protein degraders . They have made ACBI2 freely available to any institution that requests it . In summary , the research team has synthesised ACBI2 , a new and exciting anti-cancer molecule that targets disease-causing proteins for destruction by the body's immune system . The novel drug offers several advantages over classic enzyme inhibitors . The scientists tested ACBI2 in mice and in several cell lines , finding that the molecule significantly inhibited tumour growth in mice bearing lung cancer , the team has agreed to make the molecule freely available to other researchers upon request .