Case Studies from IDSC Experts
NF-kB Inhibitors for the treatment of cancer, inflammation and viral diseases
- Several novel classes of low molecular weight compounds were identified that directly inhibit the binding of NF-kB components, p65 (RelA), RelB and c-Rel to DNA. As a result, these compounds can block both the canonical and non-canonical pathways of NF-kB.
- The original hits were discovered via a combination of high throughput screening, in silico screening and consideration of existing chemical matter.
- After a thorough triage and some early optimization studies, focus quickly centered on a small number of chemical series.
- Through the careful management of external CRO chemists, and over a period of just six months, several key compounds were identified that were suitable for dosing in in vivo animal models including rheumatoid arthritis.
- Results from these studies and others demonstrated that these novel compounds, and their unique mechanism of action, showed great promise as novel treatments for a number of disease states.
- This work has resulted in the filing of several patents and several presentations at key scientific meetings.
Return to top
Early Stage Preclinical Project
- Client sought to take a novel antibacterial target, and associated screening hits, forward to preclinical proof of concept with the goal of providing the data needed to support grant proposals or attract VC investment.
- IDSC examined the biological target using several criteria including essentiality, ease of access, and a "drugable" active site and found target to be good for potential drug finding.
- IDSC then examined chemical matter which was extensive 26 hits with >10 uM activity. Chemical matter was loaded with structural alerts, which are molecular features strongly associated with project failures.
- We determined that most of the leads were false and none were worthy of development.
- Client confirmed findings on selected hits and has since discussed using IDSC to evaluate the entire HTS library.
- Client saved thousands of dollars not chasing false leads but also knows that target is worthy of further effort.
Return to top
Mid Stage Preclinical Project
- Client was considering buying an antibacterial portfolio of projects and was attempting to reach a go/no-go decision on the purchase.
- IDSC evaluated the targets using several criteria including essentiality, ease of access, "drugability", ease of resistance development etc.
- Targets where prioritized on likelihood of success and resource expenditure
- IDSC further evaluated the chemical matter. Some of the most advanced hits had structural alerts which are structural features associated with historic project failures. These could be remedied and plans to go forward were offered.
- Product profiles were written listing the feature required to achieve a marketable drug.
- Current progress was checked against the product profile, action items and priorities were assigned.
- Market value of the IP currently & future potential was estimated.
- Client bought the IP and company in a multimillion dollar investment, but with clear milestones and goals based on the profiles and to do lists.
Return to top
Late stage Preclinical Project
- Client had a new quinolone type antibacterial with proof of concept. Our client, while having significant experience, need help completing a preclinical development plan.
- IDSC helped complete their product profiles
- Key compounds emerged and were evaluated for key advantages and for the ideal development path that met the spectrum, potency and pharmacology.
- IND will be written and investment and grants sought.
- Compounds are very exciting and passed all the preclinical hurdles
Return to top
Outsourcing Management
- Client engaged IDSC to manage 22 CRO chemistry FTEs and train client's internal staff
- IDSC was responsible for keeping the FTE project queue full, reviewing the literature and suggesting synthetic chemistry routes, transmitting technical packages to CRO, managing teleconferences, daily problem solving, tracking metrics, training client internal staff, and many other responsibilities.
- After one year under the IDSC guidance, the 22 CRO FTE's performance had doubled over the previous year under the client's guidance.
- Productivity enhancement resulted in significant cost savings for the client
- IDSC repositioned client to take over internal management of Outsourcing.
Return to top
Selective Norepinephrine Reuptake Inhibitors For the Treatment of ADHD - A Case Study
- Goal of developing a non-stimulant treatment for ADHD that would have limited side effects (SRI) associated with non-selective NRIs, limited drug-drug interactions related to CYP2D6 and have appropriate pharmacokinetics to allow for QD dosing.
- Several novel classes of selective NRIs were identified from high through-put screens, de novo design and existing chemical matter.
- Because of the pediatric indication, a high therapeutic index was vital. When very low levels of what appeared to be a mechanism related toxicity was noted, we successfully lobbied to have extended in vivo tox studies done much earlier than other programs - ultimately saving on expense and resource commitments.
- In 4 years, 15 chemical leads were identified - 5 were progressed through preclinical development (including extensive in vivo pharmacokinetic and toxicology studies for Phase 1 start)
Return to top
Muscarinic Agonists -- A Neurotransmitter Replacement Strategy for Alzheimer's Disease Using Molecular Modeling - A Case Study
- Derived a descriptive pharmacophore model that focused the team on productive chemical matter and resulted in a compound that went into Phase I clinical trials
- Derived a novel, predictive, non-atom-based pharmacophore model that served as an effective filter for screening candidates for synthesis
- Led to new, patentable muscarinic agonist core structure that was elaborated into an m1-subtype-selective agent
- The compound was evaluated through phase II clinical trials
Return to top
ACAT Inhibitors- A new mechanism for the treatment of hyperlipidemia and atherosclerosis - A Case Study
- Conceived and developed the strategy to convert very lipophilic ACAT inhibitors to hydrophilic ACAT inhibitors
- Synthesized, for the first time, several novel classes of hydrophilic ACAT inhibitors derived from chlorosulfonyl isocyanate
- A clinical candidate was identified within a year of project initiation
- Chemical strategy developed to address shortcomings (poor metabolic and chemical stability, polymorph formation and CYP induction) of the original clinical candidate
- Biological screening strategy developed to evaluate the utility of hydrophilic ACAT inhibitors in the intestine, liver and arterial wall.
- A second clinical candidate was identified, within 2 years of the first, and this compound, Avasimibe, advanced to phase III clinical trials for the treatment of hyperlipidemia.
Return to top
Caspase Inhibitors: A Case Study of a Medicinal Chemistry Collaboration
- Served as chemistry leader of a collaboration with a big pharma company for a caspase-1 project in the Inflammation and Neurodegeneration therapeutic areas
- Utilized high throughput screening and de novo approaches for the identification of chemical leads.
- Successfully employed x-ray crystallography and structure based drug design to develop leads.
- Identified novel, patentable peptidomimetics with high specificity for caspase-1 vs. other caspases and other cysteine proteases.
- Solved ADME issues with a prodrug approach to identify compounds active in animal models.
- Successfully identified novel pre-candidate compound.
Return to top
Quinolone Antibacterials - A Case Study
- Designed the initial proposal to work in the field
- Invented the amino and aminomethyl pyrrolidines side chains to provide the first ever Gram pos activity
- Poor in vivo was overcome with 8-halogen invention
- Phototox from 8-halogen was fixed by solving the mechanism of phototox, developing a model, and adding the 8-methoxy
- CV, genetox, and glucose lowering side effects were ID'd and solved by SAR to generate three clinical compounds one of which completed phase 3
- Invited to publish key reviews of the field
Return to top
HIV protease inhibitors - A Case Study
- Led the effort to take a 10,000 nM HTS non peptide hit to clinical compound
- Arranged modeling collaboration to get crystal structure with hit docked
- Iteratively improve potency to 0.2 nM (50,000 fold) in 14 months
- Poor cellular activity was found to be from protein binding
- Protein binding was overcome by modeling the binding and designing compounds around it
- PK was optimized further to give a BID compound with zero cross resistance
- Compound completed phase 1, three years from HTS
