The recommended dose is yet to be established Two candidates from Pfizer are currently being developed, one for i.v. administration, and one for oral dosing PF 05212384. Both compounds are dual PI3K/mTOR inhibitors and show acceptable pharmacokinetic profiles after 3 dose escalations. So far no clinical activity has been reported. Pharmacodynamic biomarker assessment

AC-220 Quizartinib by measurement of glucose and insulin levels in blood. Nausea, fatigue, headache and hyperglycaemia have been the most frequently reported treatment related adverse events so far. Dose escalation is ongoing for both compounds 5.3. p110??Selective PI3K Inhibitors The potent p110??specific inhibitor CAL 101 exhibits 40 to 300 fold selectivity for that particular isoform, as compared to other PI3K enzymes and is undergoing Phase I clinical evaluation in relapsed or refractory haematological malignancies.

The first interim reports from phase I trials with CAL 101 show promising drug activity and a lack of severe toxicity in haematological cancer patients. Plasma exposure was shown to increase with dose. AKTTHR308 as a marker of PI3K activation was measured AZD8931 in cells from a subset of chronic lymphocytic leukaemia patients with circulating lymphocytes and was observed to be reduced by 90% following dosing, demonstrating target inhibition. 6. SUMMARY AND FUTURE PERSPECTIVE As mentioned earlier in this review, the progression of PI3K inhibitors over the last twenty years or so has been remarkable. There are a number of interesting and important features that can be highlighted.
First is the evolution from chemical tool compounds, like LY294002 1, Wortmannin 2 and PI 103 18, to drugs that are now beginning to show pharmacodynamic evidence of target modulation and clear signs of therapeutic benefit to cancer patients. Next to highlight is the impact of the crystal structures of p110 catalytic domains, facilitating the interpretation of isoform selectivity profiles and the prospective design of desired profiles. In the landmark study by Knight et al, common selectivity combinations were identified, as with agents that exhibit preferences for p110??p110???and p110??????? Inhibitors of p110???often also inhibit the class IV isoforms DNAPK and mTOR, as with PI 103, but it has been possible to remove the class IV inhibition from class I selective inhibitors as in case of GDC 0941 3 compared to PI 103.
The desirability of p110??pan class I isoform selectivity for cancer therapy is still being debated. It is now clear that highly selective inhibitors of p110???can be produced and that p110??????inhibitors can also be obtained, for potential use in inflammation. Many variations on these core patterns exist. Although mouse models will help, it is likely that the preferred isoform selectivity profiles for medical use, as distinct from chemical tools, will only emerge following detailed clinical evaluation of multiple agents. For future drug design, the SAR rules for achieving selectivity are progressively being defined, facilitated by the increasing availability of crystal structures.