EFMC-ISMC 2024 Preview

Hello, we're back with another preview of the EFMC-ISMC 2024 conference sessions.

EFMC-ISMC2024 is an international medicinal chemistry symposium taking place September 1-5 in Rome, Italy, and is divided into three main sessions: Chemical Biology, Drug Discovery Projects, and Technologies.

Chemical Biology

Tackling “Difficult-to-Drug”-Targets with Chemical Biology Approaches

Next-Generation Covalent Drug Discovery (LE001)

Covalent docking, Kinome-wide activity

Covalent drugs were originally difficult to develop due to difficulty in predicting side effects and lack of technology. However, in the last decade, advances in crystallography, computational/organic chemistry, and bioinformatics have steadily increased the number of covalent drugs from 2% to up to 11% of FDA-approved drugs each year. Recently, PROTAC has also seen an increase in research using covalent warheads, and the importance of covalent drug development in new modalities is growing.

In line with this research trend, HITS is also developing a model to predict the activity of covalent drugs. We currently have an R2 = 0.7, an achievement in just four months. We will continue to improve its performance and bring it to the hyper Lab later this year. In addition, a program to help improve selectivity by predicting which kinases a single inhibitor will be active on kinome-wide will be released later this year.

Targeting RNA and RNA-Regulatory Proteins

Hit Discovery for Riboswitches as Targets for Antibiotics (LE014)

Riboswitches

Riboswitches are parts of mRNA molecules that function to directly regulate the expression of mRNA by binding to small molecules. Riboswitches regulate gene expression by allowing certain metabolites to bind to small molecules within the cell. Riboswitches are divided into two parts: an aptamer domain that binds to specific small molecules, and an expression platform that regulates gene expression by causing conformational changes when a small molecule binds to the aptamer domain.

Riboswitches have been studied extensively, especially in bacteria, and are of interest for the development of new antibiotics. Many bacteria have riboswitches that regulate essential genes, such as the thiamine pyrophosphate (TPP) riboswitch, which regulates genes responsible for thiamine biosynthesis and transport. This can be inhibited by small molecules, which inhibits the growth of bacteria, identifying the potential to develop a new class of antibiotics.

Structure-Based Design of a Potent and Selective YTHDC1 Ligand (LE016)

YTHDC1 Ligand

N6-adenosine methylation (m6A) is known as a post-transcriptional modification of mRNA, and YTHDC1 is a protein that recognizes this modification in the cell nucleus. Through protein structure-based design, the speaker developed a YTHDC1 inhibitor with a Kd of 49 nM, whose binding structure was also validated with PDB ID 8Q4W (1.6 Å resolution). compound 40 selectively reacts with the cytoplasmic m6A-RNA leaders YTHDF1-3 and YTHDC2 and exhibits anti-proliferative activity in acute myeloid leukemia (AML) cell lines. Derivatives derived from compound 40 show a high correlation between binding at the enzyme level and anti-proliferative activity in the THP-1 cell line, demonstrating that they bind to YTHDC1 in cells. 

Chemically Induced Proximity Approaches for Therapeutic Intervention

Chemical Biology Approaches for a Quantitative Understanding of PPI Stabilization; How to Identify Molecular Glues for the 14-3-3 Interactome (LE029)

PPI

Protein-protein interaction (PPI) stabilization is increasing the stability of protein-protein interactions, which is also achieved through molecular glues. Molecular glues can selectively modulate PPIs by binding between two proteins and bringing them closer together. A well-known example is immunomodulatory imidazole drugs (IMiDs), such as talidomide, which affects the CRL4CRBN E3 ubiquitin ligase complex.

14-3-3 proteins are known to interact with a variety of signaling proteins, and the speaker has previously developed a molecular glue that selectively stabilizes 14-3-3/ChREBP PPIs. Through hotspot functional mapping and mutational studies, we developed a peptide-based molecular glue to selectively stabilize 14-3-3/ChREBP PPIs.

Drug discovery Projects

Drug Discovery Beyond the Rule of Five

Identification of TAK-756, a Potent and Selective TAK1 Inhibitor for the Treatment of Osteoarthritis Through Intra-Articular Administration (LE007)

TAK-756

TAK-756 is a potent and selective inhibitor of Transforming Growth Factor-β Activated Kinase 1 (TAK1) that is being investigated for the treatment of osteoarthritis through intra-articular administration. TAK1 plays an important role in mediating inflammatory responses and has been identified as a potential therapeutic target for a variety of inflammatory diseases, including osteoarthritis. This drug is specifically focused on reducing inflammation and pain through intra-articular administration. TAK-756 targets TAK1 to inhibit the release of inflammatory cytokines and is effective in inhibiting the pathologic process of osteoarthritis. Currently, TAK-756 is being studied in the preclinical stage and has demonstrated high selectivity and efficacy.

Self-Immolative Pleiotropic Prodrugs: an Innovative way to Treat Alzheimer's Disease? (LE008)

Self-Immolative Pleiotropic Prodrugs

Self-Immolative Pleiotropic Prodrugs (SIPPs) are emerging as a novel approach for the treatment of Alzheimer's disease. These are drugs that self-immolate in response to specific stimuli, releasing multiple active ingredients to simultaneously affect different physiological pathways. This is useful for developing multi-targeted therapies given the complex pathology of Alzheimer's.

Early Integration of Translational Strategies into Discovery Projects

Translational Biomarker Strategy for Development of MK-4334, a Novel Positive Allosteric Modulator of the α7 nAChR (LE019)

MK-4334

MK-4334 is an α7 nicotinic acetylcholine receptor (nAChR) positive allosteric modulator (PAM) developed in collaboration between Bionomics and MSD. PAMs do not activate the receptor by themselves, but bind to the allosteric site of the receptor, making the receptor more responsive to signaling molecules. The drug was developed starting with Bionomics' BNC375, which is currently in Phase 1 clinical trials and is being evaluated as a promising candidate for the treatment of cognitive disorders such as Alzheimer's and schizophrenia. It differs from existing drugs in that it avoids the side effects caused by the lack of selectivity of nAChR agonists, as well as receptor desensitization, a phenomenon in which the receptor becomes less and less responsive as the drug continues to bind to the receptor over time. (NCT03740178, NCT05136690)

Discovery of ASTX295: a Bone-Marrow Sparing MDM2 Antagonist. From Concept to Clinic (LE020)

ASTX295

ASTX295 is an MDM2 antagonist being developed by Astex Pharmaceuticals using a structure-based drug design approach. Inhibiting MDM2 restores p53 tumor suppressor function and induces cancer cell death, and the drug has been shown to be effective in patients with normal wild-type p53 but overexpressed MDM2. ASTX295 has a short half-life and minimizes the decrease in the production of blood cells in the bone marrow, reducing the risk of potential thrombocytopenia, which differentiates it from existing first-generation MDM2 antagonists. It also has improved CYP metabolism and cardiotoxicity. It has passed Phase 1 and is currently in Phase 2.(NCT03975387)

Trends in Peptide Drug Discovery

From Reversible to Irreversible Peptide Inhibitors of the TRF2TRFH Recruiting Functions: a Strategy to Induce Replication Stress in Cancer Cells (LE034)

TRF2TRFH

TRF2, one of several proteins that make up Shelterin, is an essential regulator of telomere homeostasis and genomic stability. The TRFH domain of TRF2 is a region that mediates protein-protein interactions, forming complexes with a variety of telomere-binding protein interactions. Mutations in the TRF2TRFH domain are known to cause telomere DNA damage by disrupting the recruitment of several factors, including physically impairing t-loop formation.

Therefore, we designed and synthesized a covalent cyclic peptide that irreversibly binds to the TRF2 TRFH domain cysteine and induces cancer cells to die, including inducing a telomere DNA damage response, increasing telomere replication stress, and disrupting the interaction of RTEL1 and SLX4, two proteins that play important roles in telomeres. The researchers experimentally demonstrated that APOD53 inhibits cancer cell growth, but also showed that treatment with the G4 stabilizer RHPS4 and a low dose of aphidicolin (APH) maximized telomere replication stress, revealing the benefits of co-administration.

Evolution Towards Clinical Candidate MK-0616: Next Generation Oral Tricyclic Peptide PCSK9 Inhibitors for LDL-Lowering and Coronary Heart Diseases (LE035)

PCSK9

PCSK9 is a protein produced by the liver that plays an important role in lowering LDL cholesterol levels in the blood by promoting the degradation of LDL cholesterol receptors. Excessive activity of PCSK9 increases the risk of hypercholesterolemia and cardiovascular disease, and inhibition of PCSK9 has emerged as an important strategy for the treatment of hypercholesterolemia.

The speaker will introduce a study of PCSK9 inhibition with the MK-0616 peptide, which increases LDL receptors and promotes their degradation. In a Phase 2b clinical trial, we have demonstrated a significant reduction in LDL-C in hypercholesterolemic patients, which is orally administered, which is differentiated from the existing therapies, which are all injectable.

Technologies

DNA-Encoded Libraries / ACSMEDI Session

Recent Advances in DNA-Encoded Library Technologies at GSK (LE022)

Using DEL for Targeted Protein Modulation (LE023)

DEL

DNA Encoded Library (DEL) is a technique for building compound libraries and screening compounds at high speed. It combines compounds and DNA sequencing to efficiently explore a wide range of compounds and help identify drug candidates.

Each compound is paired with a unique DNA barcode, which allows the compound to be identified and tracked. The resulting library of millions of compounds is then reacted with a target protein. The bound compound-protein complexes are isolated, and the DNA barcodes are sequenced to determine which compounds have bound to the target. This allows potential drug candidates to be quickly identified.

Macrocyclic MCL-1 Inhibitors: an Efficient Combination of DNA-Encoded Library Screening, Parallel

Macrocyclic MCL-1 inhibitors

MCL-1 (Myeloid Cell Leukemia 1) belongs to the BCL-2 protein family and plays an important role in regulating apoptosis. Specifically, it promotes cell survival by inhibiting pro-apoptotic proteins such as BAX and BAK. Therefore, overexpression of MCL-1 is commonly observed in various cancers, especially leukemias, lymphomas, and solid tumors, which contributes to the survival of cancer cells and their resistance to chemotherapy.

Macrocyclic inhibitors have a large, ring-shaped molecular structure, which can lead to improved binding specificity and potency with target proteins. These inhibitors often have improved oral bioavailability and metabolic stability. Macrocyclic inhibitors bind to the BH3 binding groove of MCL-1 and block its interaction with pro-apoptotic proteins. This results in activation of the apoptosis pathway, leading to selective death of MCL-1-dependent cancer cells.

The speaker is a medicinal chemistry team leader at Symeres and will discuss his work in discovering MCL-1 inhibitors using the DEL methodology.

Computational Chemistry and Computational Biology in Drug Discovery

Discovery of HRO761, a First-In-Class Allosteric WRN Inhibitor by Property-Based Design Using AB Initio Conformational Analysis (LE039)

HRO761

HRO761 is a Werner syndrome RecQ helicase (WRN) inhibitor being developed by Novartis that primarily targets microsatellite instability (MSI) cancer cells. WRN has been identified as a synthetic lethal target in MSI cancer cells through multiple genetic screens. HRO761 selectively inhibits this WRN protein to inhibit DNA damage and tumor growth in MSI cancer cells. HRO761 binds between the D1 and D2 domains of the WRN protein, locking WRN in an inactive state. This makes it selective, degrading WRN only in MSI cancer cells and not in microsatellite stable (MSS) cells. Property-Based Design and Ab initio Conformational Analysis played an important role in the development of this compound, a methodology that uses quantum mechanics to predict the structure and energy of a molecule and design a molecule with the desired properties. A Phase I clinical trial is currently underway to evaluate the safety of HRO761. (NCT05838768)

That's a quick recap of our sessions at EFMC-ISMC 2024. HITS will also be exhibiting at EFMC-ISMC 2024, and we'll be introducing Hyper Lab, our AI drug discovery platform that uses AI to create the medicines the world needs faster. We look forward to seeing you at booth #4.