Tips for Aspiring Drug Discoverers

It takes courage to address common pitfalls in drug discovery and perseverance to traverse the route.

In my work and as an advisor I’ve seen 100s of early-stage drug discovery programs. Watching so many projects as they move through the different stages is enlightening.  The tips below are for aspiring drug discoverers, academics or new start-up founders. It’s for those who have a great idea for a new therapeutic and want to avoid common mistakes.

These common pitfalls include compound issues (mostly for small molecules), translational issues, and business issues. Addressing and planning for these at an early stage will pay off, not only in savings of time and money, but also in the research group’s prospects for the future.

Compound issues.

Common issues for compounds: (1) the compound is not potent enough; (2) it is not selective enough; and/or (3) it is not drug-like enough. In early discovery, compound potency is most often assessed using biochemical or recombinant assays. Potency tends to decrease as the testing system becomes more complex. For compounds with a biochemical potency of 10 nM, potency in a cell-based assay may be 100 nM, and efficacy in vivo may require exposures (e.g., Cmax or maximal concentration) of 1 µM. It may be helpful to note that the median Cmax of approved drugs is ~ 2 µM. Keep in mind that drug exposures in people are also known to vary by 5-10-fold among individual patients. Compounds that are either weaker in cells (20-100-fold weaker) or more potent than in biochemical-based assays can signal a problem. Unexpectedly high potency in cell-based assays can result from undesirable off-target activities. Off-target effects that add potency due to untoward mechanisms include microtubule inhibition or interference with lysosomes. These effects are surprisingly common and found in many approved drugs (limiting dosages at which these drugs can be given). Note: covalent type drugs or drug with certain enzymatic features may be an exception to this.

Lack of sufficient target selectivity is also a common problem. Target selectivity is most often assessed relative to structurally related targets using biochemical or recombinant assays. As with potency, target selectivity windows of 10-100-fold can drop substantially (down to 2-10-fold) when tested in more complex, biologically relevant assays. The “selectivity” of a compound’s activity relative to cell cytotoxicity or other safety-related endpoint is also an important measure for successful drugs. This can be calculated as an in vitro safety margin. The margin of safety or therapeutic index is the ratio of the amount of drug required for efficacy compared to the amount that causes toxicity. For a rule of thumb, we recommend that the in vitro safety margin for adverse effects in cell-based assays (e.g., efficacy versus cytotoxicity) should be >300 fold. While this seems high, keep in mind that as systems become more complex (in vivoversus in vitro), safety margins will decrease.

Potency and selectivity for the target is only the beginning. A successful drug must also get to the tissue site of action, stick around long enough to have an effect, and avoid interfering with unrelated biological processes that cause toxicity. Often first-time drug discovery researchers don’t appreciate how much chemistry and further testing goes into lead optimization to develop a successful drug. It is not easy make modifications to improve potency, selectivity, and bioavailability without running into safety issues.

Translational issues.

Animal models are often used to make go/no-go decisions for disease validation. This happens despite wide acknowledgement that animals are generally poor predictors of human efficacy. Successful drug programs do not depend on animal validation but rely instead on developing a strong chain of translatability. The chain of translatability is comprised of mechanistic connections between the molecular target and the clinical outcome.  Supporting clinical translatability can be accomplished by using human cell-based or tissue models of the disease and measuring clinical biomarkers or signatures (protein, metabolite or transcriptional profiles). These connect the molecular target to the biological processes at work in disease tissues and subsequently to endpoints measured in clinical studies. We’ve previously discussed how Discovery Program Outcome Pathway frameworks can help build the chain of translatability. By applying this framework early in the discovery process, knowledge gaps about the disease and the target can be identified. Assays and research performed to fill in these gaps can reduce program risks and lead to alternative directions.

Business issues.

Understanding what is valuable about your program (and to whom!) can be challenging for first time drug discoverers. There is a tendency to focus on intellectual property claims around a drug lead. Keep in mind that early-stage assets start out with negative financial value (negative NPV). This is because drug development costs many millions of dollars and the likelihood of success is low. Thus, to create value, consider how you can reduce the risk and increase the probability of success for a given amount of investment. Developing a novel platform, or unique insights into disease mechanisms can build value. Novel assays make good assets too. Multiple lead candidates can reduce the risk of compound-specific failures. Alternative targets can reduce the risk of target-specific toxicity derailing your program.

Quick takeaways.

• Your lead is not a drug.  A drug is a lead + $100M in optimization and development costs (not including costs of failed leads).
• You will be wrong about the biology.  Build “learning” into your program.
• Your first project will not be successful.  Always have a plan B (another lead, another target, another program).

Now go forth and tackle those switchbacks!

Photo by Patrick Hendry on Unsplash.