Lead Development and Optimization

The Lead Development and Optimization shared resource, led by Divya Kamath, PhD, provides access to expertise in target identification and validation, screening compounds, preclinical candidate development, drug delivery and preclinical proof-of-concept animal studies. The Lead Development and Optimization shared resource is a key asset supporting discovery and development activities of researchers at The University of Kansas Cancer Center.

The Lead Development and Optimization shared resource has 6 aims:

1. Aid cancer center members in designing and implementing research studies that generate critical data to reach in vivo proof-of-concept quickly and cost effectively.
2. Provide project management expertise to facilitate transdisciplinary project activities.
3. Provide methods development, optimization, validation and large compound library high-throughput screening with hit ID, confirmation and prioritization.
4. Provide medicinal chemistry, cell-free protein production expertise and resource identification for preclinical candidate progression. 
5. Provide drug formulation, delivery, dosage-form development and early absorption, distribution, metabolism and excretion (ADME) expertise.
6. Interface with the Drug Discovery and Development Steering Committee, the Institute for Advancing Medical Innovation and the Investigator-Initiated Trial Steering Committee to achieve advancement of novel therapeutic agents from bench to bedside.
   
   

Cancer center members, as well as other industry partners and researchers at other cancer centers, have access to these services. The shared resource is comprised of 3 components that provide discovery and development support of novel cancer therapeutics in the following preclinical space:

High-Throughput Screening Laboratory (HTS): Research and development focuses on target selection and validation for high-throughput method development and compound probe screening. For information, contact Anuradha Roy at anuroy@ku.edu. Key services include: 

• Assay method development for biochemical, biophysical or phenotypic screens 
• Assay optimization for HTS adoption and assay validation
• Large compound library HTS (~400,000 compounds)
• Hit identification/confirmation/ prioritization and hit to lead assay

Medicinal Chemistry (MDCM): Research and development focuses on lead optimization through synthesis chemistry, chemical biology and emerging small-molecule therapeutic modalities. Also, supports peptide and cell-free protein and mRNA synthesis. For information, contact Raul Neri-Sierra at rnerisierra@kumc.edu. Key services include: 

• Medicinal chemistry compound synthesis for hit-to-probe, probe-to-lead and lead-to-preclinical candidate progression
• Structure-activity and structure-property relationship optimization
• Peptide synthesis and cell-free protein synthesis 

Biopharmaceutical Innovation and Optimization Center: Research and development focuses on conventional and novel drug delivery and animal pharmacokinetic support. For information, contact Michael Hageman at mhageman@ku.edu. Key services include: 

• Bioanalytical method development, compound solubility and stability enhancement
• In vitro pharmacology testing
• In vivo pharmacokinetic and tissue distribution testing 
• Drug substance and dosage-form development and analysis and drug delivery 

This multicomponent shared resource at the cancer center is unique in an academic setting with state-of-the-art equipment and highly trained, experienced scientists to support cancer research toward target validation and the development and optimization of lead compounds. The Lead Development and Optimization shared resource works closely with the Institute for Advancing Medical Innovation not only to shepherd projects smoothly into the pipeline, but also to ensure that once optimization is complete, these projects are supported by clinical and product development colleagues.

HTS Cytotoxicity Screen for Pediatric Diffuse Intrinsic Pontine Gliomas (DIPGs) Using Paired DIPG Cell Lines 

Diffuse Intrinsic Pontine Gliomas (DIPGS) are a deadly pediatric cancer with a very low survival rate. This study uses high-throughput screening (HTS) to test 2,939 compounds from an FDA/Bioactive library on DIPG cell lines with a specific genetic mutation. After testing, 86 compounds showed promise, and 12 were found to specifically target the mutated cells. The compounds showed significant cytotoxicity against the DIPG cells compared to normal control lines.

Rationally designed Nanosponges for Gemcitabine Delivery (Nano-Gem) to Cholangiocarcinoma 

This research aims to improve the treatment for cholangiocarcinoma (CCA) by using a special drug delivery system to target the liver and biliary tract with gemcitabine. Gemcitabine is a chemotherapy drug already approved by the FDA for use. The Nano-Gem system is being tested for its ability to safely and efficiently delivery gemcitabine directly to CCA tumors. This system is scalable, uses a polypeptide delivery method and can be manufactured under GMP conditions.

Biopharmaceutical Innovation and Optimization Center Delivers a Solid Dosage for CD206 Inhibitor for Sarcomas 

This project focuses on developing an oral solid dosage form of an investigational CD206 modulator for treating sarcomas. Four potential drug forms were tested in vivo, from which a milled tablet formulation with good dissolution properties was selected. Currently, the formula is being tested in canine osteosarcoma patients to support a comparative oncology preclinical proof of principle. 

This resource is funded by The University of Kansas Cancer Center Support Grant (CCSG) awarded by the National Cancer Institute (P30 CA168524). Publications that have utilized facility resources, services or scientific data generated by the resource should acknowledge the resource and cite the NCI CCSG grant.