Research | smondal

We are a chemical biology research group. Our objective is to integrate chemistry and biology to address diverse biomedical problems. Currently we are focused on three major areas:

Drug Development against Therapy-resistant Cancers: Although numerous cancer therapies are developed to date, a key challenge is the emergence of resistance mechanisms that evade the toxicity of anticancer drugs. Cancer cells exploit different pathways, including up- or downregulation of certain proteins/enzymes to resist the cell death mechanisms. To treat therapy-resistant cancers, we are developing novel drugs that inhibit or degrade proteins/enzymes associated with the therapy-resistance.

Precision Delivery of Cancer Therapeutics: Chemotherapeutics are one of the major therapies used to treat a variety of cancers. However, often times, chemotherapeutics require cancer cell-targeting moieties, such as monoclonal antibodies, integrin-binding ligands and receptor agonists to selectively kill cancer cells. We are pursuing this project to develop novel drug delivery platforms to precisely deliver chemotherapeutics in the cancer cells.

Drug development against Protein Aggregation Disorders: Protein aggregation is at the forefront of several amyloid diseases, including Parkinson's disease, Alzheimer's Disease, systemic amyloidoses, Amyotrophic Lateral Sclerosis and many more. We are pursuing this project to develop small molecule drugs that inhibit the aggregation of amyloidogenic proteins by targeting different species in the amyloidosis pathway. We are also interested in developing drugs that remove the toxic amyloid aggregates from the body.

Our drug development science relies on various chemical biology principles. A few major ones are showcased below:

Covalent Modification of Proteins: Proteins contain several nucleophilic amino acids that can react with electrophilic warheads. Covalent modification of a reactive amino acid in a target protein (POI) is accomplished by installing a suitable warhead on a ligand of the POI. The ligand not only brings the warhead close to a reactive amino acid but also leads to selective targeting of the POI in the presence of a complex

proteome. Covalent drugs have higher residence time on a POI, and are extremely useful to target pathogenic mutants that contain a nucleophilic substitution (e.g., oncogenic KRAS G12C).

Activity-based Protein Profiling (ABPP): ABPP takes advantage of the covalent ligands functionalized with an alkyne that can be conjugated with various reporter tags (e.g., fluorophore, biotin) using bio-orthogonal coupling chemistries (e.g., copper-catalyzed click chemistry). While fluorescent tags enable the detection of a POI, biotin tags enable affinity enrichment and proteomic identification of the cellular targets of a covalent drug. ABPP also enables monitoring cellular target engagement and high-throughput screening to identify novel ligands of a POI.

Targeted Protein Degradation (TPD): The overarching theme of TPD is artificially hijacking the cellular protein degradation machineries, such as proteasome and lysosome using chimeric bifunctional molecules (in most cases). Proteolysis targeting chimeras (PROTACs) comprises the ligands of a POI and an E3 ligase connected with an appropriate linker, facilitating the recruitment of a

E3 ligase to a POI and polyubiquitination of the latter. Subsequently, the POI is degraded by proteasome upon recognition of the polyubiquitin chains. Similarly, several bifunctional molecules, including LYTACs, AUTACs and ATTECs are known that artificially mediate the lysosomal autophagy of POIs (J. Med. Chem. 2021, 64, 3493).

Photopharmacology: A major challenge in drug development is to achieve the selective action of the drugs at the desired tissue (e.g., tumor), lack of which leads to toxicity. Therefore, selective activation/delivery of a drug at a target tissue in response to an external or internal stimuli is of paramount interest. We particularly leverage light, which is a noninvasive external stimuli and can be delivered to a target tissue with high spatiotemporal precision for the selective activation/delivery of the drugs at their site of action.