Enzyme inhibitors

We synthesise powerful inhibitors of therapeutically relevant nucleoside processing enzymes based on experimental knowledge of the enzyme transition states.

PNP in enzyme active
DADMe-Immucillin-A, modelled inside the active site of human purine nucleoside phosphorylase

Treatments for unmet medical needs

This significant research programme is a 20-year collaboration with Professor Vern Schramm, Department of Biochemistry, Albert Einstein College of Medicine (Einstein), Yeshiva University.

In the search for new therapeutics to treat diseases such as cancer, gout, malaria and microbial infections, we have designed and synthesised potent enzyme inhibitors of a number of target enzymes. Several inhibitors have been licensed to drug companies and progressed through to Phase IIb clinical trials.

The collaboration has brought in approximately $20 million in licensing revenue to date.

Approach

Our unique approach involves the design and synthesis of nature-like compounds, which mimic the stereoelectronic properties of a chosen enzyme’s active site, at its transition state.

These properties are determined experimentally—a method that enables the design of compounds that bind extremely tightly—and produce inhibition constants (Ki*) in the femtomolar to picomolar range. This is effectively irreversible binding, and a single oral dose of such an enzyme inhibitor (in mice or humans) results in complete inhibition of the target enzyme for its lifetime in a cell.

Our enzyme-specific inhibitors therefore have the potential to be more effective and have fewer side effects than other therapeutic agents.

Professor Vern Schramm named this brand new class of enzyme inhibitors ‘immucillins’—penicillin for the immune system.

The process

We work closely with the biological scientists at Einstein to:

  • identify an enzyme (Einstein and Ferrier)
  • determine the transition state structure (Einstein)
  • design a target inhibitor (Einstein and Ferrier)
  • synthesise inhibitors (Ferrier)
  • testing (Einstein).

All intellectual property arising from the research is jointly owned. Our involvement is managed by Dr Shivali Gulab.

Publications and patents

The collaboration has given rise to more than 80 peer reviewed publications in major journals and 30 patent families.

Staff

Prof Peter Tyler (programme lead) | Dr Keith ClinchProf Gary Evans | Dr Lawrence Harris | Jennifer Mason.  

Current research projects

We are synthesising targets as potential inhibitors of the following therapeutically relevant enzymes:

  • DNA methyltransferase: to reduce DNA methylation and alter gene expression with an anti-cancer effect.
  • CD38: an enzyme that makes and hydrolyses cyclic ADP ribose—an important intracellular signalling molecule.
  • Methylthioadenosine nucleosidase and phosphorylase: synthesising new analogues of these potent inhibitors as anti-cancer and anti-infective agents.
  • Saporin: preparing an antidote for the potent toxin saporin to enable its use in cancer treatment.

Some of these projects are suitable for postgraduate research projects, including Masters and PhD theses. Please contact Dr Alison Daines for more information.

Forodesine™

Our first immucillin, Forodesine™ (Immucillin-H), is a 56 pM inhibitor of purine nucleoside phosphorylase. It is designed to slow down the overactive T-cell proliferation seen in T-cell cancers, T-cell mediated autoimmune diseases (such as psoriasis, rheumatoid arthritis and multiple sclerosis) and transplant rejection.

Forodesine™ showed promise in clinical trials for treating T-cell leukemias and cutaneous T-cell lymphoma (CTCL). While a pivotal Phase IIb clinical trial in CTCL achieved less than the hoped for response rate, it is the subject of a continuing clinical trial.

References

One-third-the-sites transition-state inhibitors for purine nucleoside phosphorylase, Biochemistry (1998).

Preclinical and clinical evaluation of Forodesine in pediatric and adult B-cell acute lymphoblastic leukemia, Clinical Lymphoma, Myeloma & Leukemia (2013).

Ulodesine

The second generation immucillin Ulodesine (DADMe-Immucillin-H) is a 9 pM inhibitor of purine nucleoside phosphorylase.

In a Phase IIa study of patients with psoriasis, it was found to be safe and well-tolerated but did not show adequate clinical efficacy. It has since completed a successful Phase IIb trial in combination with allopurinol for treating severe gout.

Reference

Achieving the ultimate physiological goal in transition state analogue inhibitors for purine nucleoside phosphorylase, Journal of Biological Chemistry (2003).

MTDIA

The second generation immucillins in the MT-DADMe-Immucillin-A series such as MTDIA, are powerful inhibitors of human methylthioadenosine phosphorylase.

MTDIA is currently in pre-clinical development for the treatment of triple negative breast cancer.

Compounds in this family also inhibit the bacterial enzyme methylthioadenosine nucleosidase. As a consequence, they block AI-2 mediated block quorum sensing in bacteria and have potential as anti-infectives for human and animal use. The disruption of biofilm formation by the pathogenic bacteria responsible for infections associated with joint implants has been demonstrated.

Other analogues that block the biosynthesis of menaquinone in a limited set of bacteria are in pre-clinical development as treatments for chronic Helicobacter pylori infections associated with duodenal ulcers and cancers.

References

Transition state analogue inhibitors of human methylthioadenosine phosphorylase and bacterial methylthioadenosine/S-adenosylhomocysteine nucleosidase incorporating acyclic ribooxacarbenium ion mimics, Bioorganic & Medicinal Chemistry (2012).

A picomolar transition state analogue inhibitor of MTAN as a specific antibiotic for Helicobacter pylori, Biochemistry (2012).

Femtomolar inhibitors bind to 5’-methylthioadenosine nucleosidases with favorable enthalpy and entropy, Biochemistry (2011).

DADMe-Immucillin-G

This compound is a potential malaria drug. It inhibits the purine nucleoside phosphorylases of both the human host and the parasite responsible for malaria, Plasmodium falciparum.

This activity prevents the parasite harvesting from the human host the purines that are essential for its replication. So far, it has proven effective in treating P. falciparum infection in primates.

Reference

Plasmodium falciparum parasites are killed by a transition state analogue of purine nucleoside phosphorylase in a primate animal model, PLOS ONE (2011).