How not to discover a drug - integrins

ABSTRACT

Introduction. Integrins are a family of 24 cell adhesion receptors that play a role in the biggest unmet needs in medicine – cardiovascular disease, immunology and cancer. Their discovery promised huge potential for the pharmaceutical industry.

Areas covered. Over 35-years since their discovery, there is little to show for the hundreds of billions of dollars of investment in anti-integrin drug discovery programmes. In this review the author discusses the reasons for the failure of this promising class of drugs and the future for this class of drugs.

Expert opinion. Within 10-years, there was a plethora of potent, specific anti-integrin molecules and since their discovery, many of these agents have entered clinical trials. The success in discovering these agents was due to recently discovered monoclonal antibody technology. The integrin-recognition domain Arg-Gly-Asp (RGD) provided the basis for discovering small molecule inhibitors to integrins – both cyclic peptides and peptidomimetics. Most agents failed in the Phase III clinical trials and those agents that did make it to the market were plagued with issues of toxicity and limited efficacy and were soon replaced with non-integrin targeting agents. Their failure was due to a combination of poor pharmacokinetics and pharmacodynamics, complicated by the complex pathophysiology of integrins.

KEYWORDS:

• Platelets
• cancer
• immunology
• pharmacology
• pharmacokinetics
• pharmacodynamics
• drug discovery
• integrins

Article Highlights

• Integrins are a family of cell adhesion molecules with critical roles in cardiovascular disease, immunology and cancer making them a drug target with great potential.

• Many very potent and highly specific inhibitors were discovered and tested clinically.

• Most failed in the clinical trials and those that made it to the market had problems with toxicity and bioavailability.

• Many agents were not pure antagonists as they had agonist-like activity and are probably better described as biased agonists

• Many of the small molecule antagonists were not really once-a-day formulations

• The combination of poor pharmacokinetics and pharmacodynamics along with the complex pathophysiology of integrins ultimately led to their failure

Understanding the reasons for their failure will make it possible to develop a new generation of anti-intgrins

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.