Every life-changing drug represents the dedication of countless scientists. Developing a small molecule into a feasible drug is a complex journey, requiring deep disease understanding and rigorous cycles of design, synthesis, and validation. This process, often spanning over a decade and costing billions, faces significant challenges.

Viva Biotech has established a one-stop integrated drug discovery platform to overcome the complexities of drug discovery. By bringing together expert teams across biology, chemistry, and related fields, we've built an efficient, innovation-driven R&D environment. This platform enables small molecule development from target identification to preclinical candidate (PCC) selection, offering comprehensive drug discovery solutions. We are launching a case study series to showcase the platform's ability to accelerate drug discovery and drive partner success.

Project Background：Driving First-in-Class (FIC) Oncology Drug Discovery

Our first case study details a collaboration with a global biotech company developing novel small molecule inhibitors targeting tumors with specific gene deletions via synthetic lethality. Despite the target's therapeutic potential, early compounds faced challenges including poor chemical structures, cellular adaptation, and unfavorable drug metabolism. To overcome these bottlenecks, our partner collaborated with Viva Biotech, utilizing our expertise and technology platforms to accelerate their project with significant clinical potential.

Project Achievements：From Target to PCC in Just 3 Years

By integrating our biology and chemistry expertise, Viva Biotech facilitated rapid progression from screening to co-crystal structure in 6 months, lead compound identification within 1 year, and clinical candidate compound selection in 3 years. This effort enabled our client to develop a FIC, mechanism-based anti-cancer drug to late-stage clinical trials.

Phase 1: Fragment Screening
Efficient Screening of Proprietary Fragment Libraries

To expedite candidate compound development, Viva Biotech conducted a parallel screening approach using both the client's compounds and our proprietary fragment-based library to identify new hit compounds. Employing a fragment-based drug discovery (FBDD) strategy, our team found small molecules that bind to the target protein. Utilizing this strategy and a proprietary library of 2,000+ fragments, we employed affinity selection mass spectrometry (ASMS) to assess binding affinity to the target protein. This process identified 31 initial fragments, which were further validated and filtered by using enzyme inhibition assays and surface plasmon resonance (SPR) technology.

While Compound 1 was identified as an initial hit, its target inhibitory activity was limited (IC₅₀=620μM). To enhance potency, a structure-based similarity search and subsequent screening of 54 related compounds led to the identification of Compound 2. This is a promising lead compound with a significant increase in enzymatic inhibition (IC₅₀=1.5μM) and strong SPR binding affinity (Kd=70μM). Compound 2's novel structure was prioritized for further research and development.

Phase 2: From Hit to Lead Optimization
Co-crystal Structure Solved in 6 Months, Lead Compound Identified in 1 Year

To further enhance the potency and selectivity, co-crystal structure analysis was employed to identify Compound 2's bingding at allosteric site of the target, rather than the catalytic active site. Utilizing Viva Biotech's extensive experience in protein production and structure-based drug design (SBDD), with over 2,000 targets had been studied and 82,000+ structures had been delivered, we optimized the molecule by optimizing hydrophobic interactions and hydrogen bonding for improved target binding. The final optimized compound demonstrated a significant reduction in IC₅₀ to 8nM in target enzyme activity assays and approximately 100nM in HCT116 cell assays, exhibiting a strong selectivity for tumor cells with specific gene deletions.

Phase 3：From Lead to PCC
Enhancing Druggability with SBDD

Following lead compound identification, co-crystal binding mode studies and SBDD were utilized to improve target inhibitory activity and selectivity. Optimization focused on precise molecular substituent modifications. Refinement of R1, R2, R3, and R4 substituents improved solubility, stability, and bioactivity. 

Specifically, piperidine incorporation at R1 enhanced solubility and permeability, R2 optimization improved binding affinity, R3 aromatic groups increased stability, and R4 modification reduced PBB and enhanced bioavailability. Subsequently, Viva Biotech's chemistry team further optimized the R4 substituent, resulting in a compound with excellent pharmacokinetics, safety, and in vivo antitumor activity, leading to its selection as the PCC.

Viva Biotech's expertise in fragment-based screening, protein production, and structural research was pivotal. By leveraging our proprietary fragment library, we rapidly identified potential active molecules and employed protein co-crystal structure analysis to accelerate compound optimization. This integrated approach not only expedited the discovery of the lead compound but also significantly enhanced the druggability of the final candidate, ultimately driving the successful delivery of this project.

Viva Biotech's One-Stop Integrated Service Platform, Accelerating FIC Drug Discovery with a Comprehensive Platform

Comprehensive One-Stop Service Capability

Viva Biotech's integrated multi-platform and advanced AIDD/CADD technologies. Leveraging our deep expertise in FIC drug development and a team of experienced scientists, we provide customized, one-stop solutions to global biotech and pharmaceutical partners.

Comprehensive Drug Discovery Platform and Structurally Diverse Proprietary Compound Library 

Equipped with a range of advanced screening technologies, we offer screening capabilities based on both our proprietary compound library and client-provided libraries. The design of our compound library takes into full consideration structural diversity, physicochemical properties, drug-likeness, and solubility. Additionally, it undergoes continuous optimization by a team of experts in medicinal chemistry, computational chemistry, and drug screening.

High-Performance Protein Research Platform for Complex Structure Analysis

Our industry-leading protein research platform excels in resolving complex structural challenges. Leveraging deep expertise, we provide customized, precise solutions tailored to our clients' specific requirements.

If you are interested in Viva Biotech's one-stop integrated drug discovery platform, please visit https://www.vivabiotech.com or contact our expert team at info@vivabiotech.com for further discussion.