A wee1 bit of information: Project Introduction

The WEE1 kinase is a critical cell cycle regulator, playing a pivotal role in the G2 checkpoint to prevent cells with DNA damage from entering mitosis. Targeting WEE1 has emerged as a promising strategy in cancer therapy, as its inhibition can enhance the efficacy of DNA-damaging agents and induce synthetic lethality in tumors with specific genetic backgrounds. This project, which is at the forefront of innovation, seeks to identify and characterize novel WEE1 inhibitors that can be developed into potent therapeutic agents. Through high-throughput screening, computational modeling, and biochemical assays, we aim to discover compounds that effectively inhibit WEE1 activity. The successful identification and optimization of these novel inhibitors could revolutionize cancer treatment by providing new options for combination therapies and overcoming resistance to existing treatments.

This project is a collaborative project between MEDCHEM.fi, UP-lab, and Aurlide Ltd.

Project Introduction

Epidermal Growth Factor Receptor (EGFR) mutations are frequently implicated in various cancers, with specific mutations leading to resistance against first- and second-generation EGFR inhibitors. The triple-mutant EGFR, particularly the T790M/C797S/L858R mutations, poses a significant challenge due to its enhanced oncogenic potential and resistance to conventional therapies. This project aims to rationally design and develop macrocyclic compounds that can effectively inhibit this triple-mutant EGFR variant. Utilizing a combination of structure-based drug design, molecular dynamics simulations, and high-throughput screening, we seek to identify macrocyclic inhibitors that can overcome the steric and kinetic challenges presented by these mutations. Our goal is to produce highly selective and potent inhibitors, offering a new therapeutic avenue for patients with resistant EGFR-mutant cancers.

This project is a collaborative project between MEDCHEM.fi and UP-lab.

We develop small molecule modulators, targeted to two mutant forms of KRAS. If you are interested in collaborating with us, obtaining funding, and developing new treatments, contact us. Here is a reminder about the importance of these mutants...

Cancer drug discovery is a complex and dynamic field that involves the identification and development of drugs specifically designed to target and treat cancer. One of the crucial steps in this process is understanding the genetic alterations that drive cancer development and progression. Mutations in genes called oncogenes, such as KRAS, play a significant role in many types of cancer.

KRAS is one of the most frequently mutated oncogenes, and mutations in the KRAS gene are particularly common in several cancer types, including lung, pancreatic, and colorectal cancers. Two prevalent KRAS mutations are the KRAS G12V and G12D mutations. These mutations involve a single amino acid change (glycine to valine in G12V and glycine to aspartic acid in G12D) within the KRAS protein.

Targeting the KRAS G12V and G12D mutations is of great interest in cancer drug discovery for several reasons that are described next.

This project is a collaborative project between MEDCHEM.fi and UP-lab.

Prevalence

KRAS mutations, including G12V and G12D, are found in a significant proportion of cancer patients, making them attractive targets for therapeutic interventions. The frequency of KRAS mutations underscores the potential impact of developing drugs that specifically inhibit these mutations.

Oncogenicity

The G12V and G12D mutations in KRAS are known to confer increased oncogenic potential, leading to uncontrolled cell growth, proliferation, and survival. Consequently, targeting these specific mutations could disrupt the signaling pathways that drive cancer development, leading to improved treatment outcomes.

Lack of effective therapies

Despite the importance of KRAS mutations in cancer, developing effective drugs that directly target KRAS has been challenging. Traditional approaches to targeting proteins with small molecules have not been successful in inhibiting KRAS mutations. However, recent advancements have shown promise in developing targeted therapies against KRAS G12V and G12D mutations, making it an active area of research.

Therapeutic opportunities

The identification of specific vulnerabilities associated with KRAS G12V and G12D mutations opens up new therapeutic opportunities. Scientists are exploring various strategies, such as inhibiting KRAS downstream effectors or exploiting synthetic lethal interactions, to develop drugs that can selectively target cancer cells harboring these mutations while sparing normal cells.

The development of targeted therapies against KRAS mutations, including G12V and G12D, is an ongoing area of research and holds great potential for improving cancer treatment outcomes. Scientists and pharmaceutical companies are investing significant efforts in unraveling the complex biology of KRAS mutations and designing innovative therapeutic approaches to address the challenges associated with targeting these mutations.

We develop macrocycle modulators, targeted to the tumor necrosis factor alpha (TNFα). Macrocycles could present a promising avenue in drug discovery for targeting TNFα due to several advantageous properties:

1. Enhanced Binding Specificity: Macrocycles offer a larger and more complex structure compared to traditional small molecules, allowing for increased specificity in binding to the target protein, such as TNFα. This specificity reduces the likelihood of off-target effects, potentially leading to safer and more effective treatments.
2. Ability to Engage Challenging Binding Sites: TNFα often features challenging binding sites that are difficult to target with traditional small molecules due to their size and complexity. Macrocycles, with their larger size and flexible structure, can more readily engage with these challenging binding sites, potentially enabling more effective inhibition of TNFα activity.
3. Improved Pharmacokinetic Properties: Macrocycles typically exhibit improved pharmacokinetic properties compared to small molecules, such as enhanced stability and longer half-lives. These properties can lead to improved drug efficacy and reduced dosing frequency, enhancing patient compliance and treatment outcomes.
4. Potential for Oral Availability: While many biological drugs targeting TNFα require intravenous administration, macrocycles hold the potential for oral availability. This route of administration is generally preferred by patients and can improve treatment adherence and convenience.
5. Cost-Efficient Discovery Methods: Despite the computational challenges associated with macrocycle discovery, advances in technology and computational methods have made the process more feasible and cost-efficient. With the development of innovative computational platforms, the discovery of macrocycle ligands targeting TNFα can be streamlined, potentially accelerating the drug development process.

In summary, macrocycle ligands offer a promising solution for TNFα targeting in drug discovery due to their enhanced binding specificity, ability to engage challenging binding sites, improved pharmacokinetic properties, potential for oral availability, and cost-efficient discovery methods. These attributes make macrocycles an attractive option for developing novel therapeutics against TNFα and other challenging drug targets.

This project is a collaborative project between MEDCHEM.fi, UP-lab, and Aurlide Ltd.

Project Description

Project Title: Rational Design and Development of Macrocyclic Compounds to Inhibit α2β1 Integrin-Collagen Interaction

Project Overview: This project aims to design and develop novel macrocyclic compounds that effectively inhibit the α2β1 integrin-collagen interaction. Building on our previous success with the small molecule inhibitor BTT-3033, we seek to leverage the unique properties of macrocycles to enhance selectivity, potency, and pharmacokinetic profiles. We aim to create new therapeutic agents for preventing and treating thrombotic diseases by targeting this interaction.

Background: The α2β1 integrin plays a crucial role in platelet adhesion and aggregation by mediating the binding of platelets to collagen in the vascular subendothelium. Dysregulation of this interaction contributes to pathological thrombosis, leading to conditions such as myocardial infarction, stroke, and deep vein thrombosis. While BTT-3033 has demonstrated efficacy in inhibiting this interaction, developing macrocyclic compounds offers several advantages, including improved binding affinity, enhanced specificity, and better pharmacokinetic properties.

Objectives:

• Design Macrocyclic Inhibitors: Utilize structure-based drug design and computational modeling to create a library of macrocyclic compounds targeting the α2β1 integrin-collagen interaction.
• Synthesize and Screen Compounds: Synthesize the designed macrocycles and perform high-throughput screening to identify candidates with high binding affinity and inhibitory activity.
• Optimize Lead Compounds: Optimize the lead macrocycles through iterative synthesis and biological testing cycles for improved pharmacokinetic properties, selectivity, and potency.
• Evaluate in Preclinical Models: Assess the efficacy and safety of optimized macrocyclic inhibitors in relevant preclinical thrombosis models.
• Prepare for Clinical Development: Advance the most promising candidates towards clinical development by conducting necessary preclinical studies and regulatory assessments.

Methodology:

1. Structure-Based Drug Design:
   • Utilize the crystal structure of α2β1 integrin and its binding interface with collagen to design macrocyclic scaffolds to disrupt this interaction.
   • Perform molecular dynamics simulations and docking studies to predict binding affinity and selectivity.
2. Synthesis and Screening:
   • Employ solid-phase peptide synthesis and other macrocyclization techniques to create a diverse library of macrocyclic compounds.
   • Use high-throughput screening assays to evaluate the inhibitory activity of synthesized macrocycles on α2β1 integrin-collagen binding.
3. Lead Optimization:
   • Conduct structure-activity relationship (SAR) studies to refine the lead compounds.
   • Optimize pharmacokinetic properties through modifications to improve stability, bioavailability, and half-life.
4. Preclinical Evaluation:
   • Test the optimized macrocyclic inhibitors in in vitro assays for platelet adhesion, aggregation, and activation.
   • Evaluate lead compounds' efficacy in animal arterial and venous thrombosis models.
   • Assess the safety profile through toxicological studies.
5. Regulatory and Clinical Preparation:
   • Prepare regulatory documentation and engage with regulatory agencies to outline the clinical development pathway.
   • Plan and initiate preclinical studies to support an Investigational New Drug (IND) application.

Expected Outcomes:

• Identification of potent and selective macrocyclic inhibitors of the α2β1 integrin-collagen interaction.
• Preclinical validation of lead macrocyclic compounds with demonstrated efficacy in thrombosis models.
• Advancement of at least one lead macrocyclic inhibitor towards clinical development for preventing and treating thrombotic diseases.

Significance: Developing macrocyclic compounds targeting the α2β1 integrin-collagen interaction represents a novel and promising approach in anti-thrombotic therapy. Macrocycles offer the potential for superior drug-like properties, including enhanced selectivity and pharmacokinetics, which could translate into more effective and safer therapeutic options for patients at risk of thrombotic events. This project aims to expand our therapeutic arsenal and improve clinical outcomes in the management of thrombotic diseases.