Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The physiological role of phosphodiesterase (PDE)11 is unknown and its biochemical characteristics are poorly understood. We have expressed human His-tagged PDE11A4 and purified the enzyme to apparent homogeneity. PDE11A4 displays K(m) values of 0.97 microM for cGMP and 2.4 microM for cAMP, and maximal velocities were 4- to 10-fold higher for cAMP than for cGMP. Given the homology between PDE11 and PDE5, we have compared the biochemical potencies of tadalafil (Cialis, Lilly-ICOS), vardenafil (Levitra, Bayer-GSK), and sildenafil (Viagra, Pfizer Inc.) for PDE11A4 and PDE5A1. PDE5A1/PDE11A4 selectivities are 40-, 9300-, and 1000-fold for tadalafil, vardenafil, and sildenafil, respectively. This suggests that none of these three compounds is likely to crossreact with PDE11A4 in patients.
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PMID:High biochemical selectivity of tadalafil, sildenafil and vardenafil for human phosphodiesterase 5A1 (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross-reaction in patients. 1599 18

Cyclic nucleotide phosphodiesterases (PDEs) have been investigated for years as targets for therapeutic intervention in a number of pathophysiological processes. Phosphodiesterase-5 (PDE5), which is highly specific for guanosine 3'-5'-cyclic-monophosphate (cGMP) at both its catalytic site and its allosteric sites, has generated particular interest because it is potently and specifically inhibited by three drugs: sildenafil (Viagra, Pfizer), tadalafil (Cialis, Lilly-ICOS), and vardenafil (Levitra, Bayer GSK). Previously, we have used [(3)H]cGMP to directly study the interaction of cGMP with the allosteric sites of PDE5, but because cGMP binds with relatively low affinity to the catalytic site, it has been difficult to devise a binding assay for this particular binding reaction. This approach using measurement of radiolabeled ligand binding continues to allow us to more precisely define functional features of the enzyme. We now use a similar approach to study the characteristics of high-affinity [(3)H]inhibitor binding to the PDE5 catalytic domain. For these studies, we have prepared [(3)H]sildenafil and [(3)H]tadalafil, two structurally different competitive inhibitors of PDE5. The results demonstrate that radiolabeled ligands can be used as probes for both catalytic site and allosteric site functions of PDE5. We describe herein the methods that we have established for studying the binding of radiolabeled ligands to both types of sites on PDE5. These techniques have also been successfully applied to the study of binding of radiolabeled PDE5 inhibitors to PDE11, suggesting that these methods are applicable to the study of other PDEs, and perhaps other enzyme families.
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PMID:Radiolabeled ligand binding to the catalytic or allosteric sites of PDE5 and PDE11. 1598 68

The protein kinase threonine tyrosine kinase (TTK; also known as Mps1) is a critical component of the spindle assembly checkpoint and a promising drug target for the treatment of aggressive cancers, such as triple negative breast cancer. While the first TTK inhibitors have entered clinical trials, little is known about how the inhibition of TTK with small-molecule compounds affects cellular activity. We studied the selective TTK inhibitor NTRC 0066-0, which was developed in our own laboratory, together with 11 TTK inhibitors developed by other companies, including Mps-BAY2b, BAY 1161909, BAY 1217389 (Bayer), TC-Mps1-12 (Shionogi), and MPI-0479605 (Myrexis). Parallel testing shows that the cellular activity of these TTK inhibitors correlates with their binding affinity to TTK and, more strongly, with target residence time. TTK inhibitors are therefore an example where target residence time determines activity in in vitro cellular assays. X-ray structures and thermal stability experiments reveal that the most potent compounds induce a shift of the glycine-rich loop as a result of binding to the catalytic lysine at position 553. This "lysine trap" disrupts the catalytic machinery. Based on these insights, we developed TTK inhibitors, based on a (5,6-dihydro)pyrimido[4,5-e]indolizine scaffold, with longer target residence times, which further exploit an allosteric pocket surrounding Lys553. Their binding mode is new for kinase inhibitors and can be classified as hybrid Type I/Type III. These inhibitors have very potent anti-proliferative activity that rivals classic cytotoxic therapy. Our findings will open up new avenues for more applications for TTK inhibitors in cancer treatment.
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PMID:Target Residence Time-Guided Optimization on TTK Kinase Results in Inhibitors with Potent Anti-Proliferative Activity. 2853 50

Rising specialty drug costs present a challenge for patients and payers. High-cost products, such as gene therapies or immunotherapies, can significantly affect the budget of a payer that does not have the ability to spread risk across a large population. Stakeholders are considering new reimbursement and benefit designs for specialty medications to improve efficiencies and better manage costs. The potential effect of changes to specialty medication benefit designs and reimbursement systems on patient care, access to medications, and the overall health care system are important considerations when assessing the benefits and challenges associated with reform proposals. Options to better manage the affordability of specialty medications are needed to ensure that patients can continue to access medications, while allowing payers to remain good stewards of health care dollars and supporting marketplace competition and incentives to stimulate innovation. New benefit designs that address these needs, while also supporting marketplace competition and providing incentives that stimulate innovation, have been considered. To explore options, AMCP convened a multidisciplinary stakeholder forum on December 10-11, 2019, in Alexandria, VA. Health care leaders representing academia, health plans, integrated delivery systems, industry leaders, pharmaceutical manufacturers, pharmacy benefit managers, employers, federal government agencies, national health care provider organizations, and patient advocacy organizations participated in the forum. The forum was designed for stakeholders to discuss strategies for the following: (a) reduce costs for beneficiaries while maintaining or improving access to prescription drugs; (b) support marketplace competition and incentives for biopharmaceutical innovation; (c) minimize physicians' financial risk associated with managing drug inventories; (d) remove adverse reimbursement incentives for prescribing higher priced drugs; (e) consider the cost-effectiveness of treatments and services across the health care continuum; and (f) support quality measurement and program evaluation metrics. Recommendations emerging from the forum included creation of novel payment models for the most expensive therapies that allow for larger risk pools, while maintaining the sustainability of the reinsurance market remains. Simplification and standardization were cited as goals for system reform and technological innovations that allow health care providers to view cost-effectiveness information at the point of prescribing, combined with value-based contracting were also recommended. Finally, ensuring that plans remain patient-centric and are designed to address patient needs holistically was stressed as an important goal. DISCLOSURES: This partnership forum was sponsored by Amgen, AstraZeneca, Bayer, GSK, Merck, Pfizer, PhRMA, Takeda, and Xcenda. These proceedings were prepared as a summary of the forum to represent common themes; they are not necessarily endorsed by all attendees nor should they be construed as reflecting group consensus.
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PMID:AMCP Partnership Forum: What's Next for Specialty Medication Benefit Design and Reimbursement. 3278 Jun 12