Lead Development and Optimization

The Lead Development and Optimization Shared Resource (LDOSR), led by Divya Kamath, PhD, supports early-stage drug discovery and development research at The University of Kansas Cancer Center. It provides expertise in target validation, high throughput screening, lead generation and optimization, analytical chemistry, formulation, novel drug delivery and preclinical drug safety, pharmacokinetics and proof-of-concept animal studies. The LDOSR is a key asset supporting the discovery and development activities of researchers at The University of Kansas Cancer Center through 4 essential aims:

1. Advance early drug discovery research through streamlining processes and collaborations.
2. Provide high-throughput automated screening technologies for drug discovery research.
3. Support medicinal chemistry optimizations and innovations for the development of novel therapeutic agents.
4. Assist with bioanalytical method development, preclinical pharmacokinetic studies and formulation development. 

Cancer center members, as well as other industry partners and researchers from other cancer centers, have access to these services. The shared resource is comprised of 3 components that provide preclinical support:

High-Throughput Screening Laboratory (HTS): HTS partners with investigators to develop and optimize HTS methods, validate HTS assays and perform screens of large compound libraries to identify, confirm and prioritize compound hits. With the help of automated/robotic technologies and curated compound libraries, HTS enables researchers to rapidly and efficiently screen large number of compounds against biological targets of interest.  For information, contact Dr. 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, hit identification, confirmation, prioritization and hit-to-lead assay
• Large compound library HTS (Nearly 409,000 compounds contained in ~12 distinct libraries)
• More than 125 human-tumor cell lines including focused sets of adults and pediatric tumor cell lines

Medicinal Chemistry (MDCM): MDCM provides medicinal chemistry support and resource identification services for lead candidate generation and optimization. MDCM supports drug discovery by providing expertise in compound design, synthesis, analysis and optimization. MDCM also supports peptide, nucleic acids and protein-based drug discovery programs. For information, contact Dr. 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 optimization
• Structure-activity and structure-property relationship optimization
• Selection of developmental candidates for early drug development
• Peptide synthesis and cell-free protein synthesis 

Biopharmaceutical Innovation and Optimization Center: BIOC provides preformulation and formulation development and in vitro and in vivo absorption, distribution, metabolism, excretion and toxicology (ADMET) services. Leveraging extensive industry experience, the BIOC team addresses drug delivery, solubility, stability and pharmacokinetic issues that typically present as barriers to project progression. For information, contact Dr. 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 drug product development analysis and delivery 

This multicomponent shared resource 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 LDOSR 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 Using Paired DIPG Cell Lines 

Diffuse Intrinsic Pontine Gliomas (DIPGS) are deadly pediatric cancers with a very low survival rate. Researchers used 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 deliver 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 evaluation. 

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.