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The PI3K/Akt/mTOR Pathway

CHI Insight Pharma Reports
November 1, 2011
SKU: CHI6709566

Abstract Table of Contents Related Reports

The PI3K/Akt/mTOR signaling cascade serves many physiological and pathophysiological functions and is of major importance in a broad array of cancers. This has stimulated substantial interest in identifying and developing modulators of this pathway. This report includes:

Pipeline reviews of PI3K, Akt, mTOR, and dual kinase inhibitors in development and an assessment of the current prospects for each approach
Role of the PI3K/Akt/mTOR cascade in various diseases and potential intervention strategies
Survey results offering unique insights into industry sentiment concerning development of inhibitors of this pathway
Profiles of selected companies that are targeting components of the PI3K signaling cascade, highlighting their distinct strategies
Significant licensing deals and acquisitions related to targeting the PI3K cascade
An overall assessment of progress in developing agents to modulate the PI3K/Akt/mTOR cascade and commercial prospects
Selected expert interviews on modulating the PI3K/Akt/mTOR cascade

In recent years it has become apparent that the activation of phosphatidylinositol 3-kinases (PI3Ks) initiates a complex sequence of intracellular events that include the activation of a number of other kinases, with Akt and mammalian target of rapamycin kinase (mTOR) both playing pivotal roles. The evidence for this PI3K cascade being heavily implicated in many types of cancer is very strong, with significant evidence for it also being important in other conditions, notably inflammatory diseases. This has led to extensive interest in the development of novel modulators of the activity of this cascade, primarily for the treatment of cancer.

The complexity of this cascade and the multiplicity of potential intervention points have prompted the structuring of The PI3K/Akt/mTOR Pathway: A Pipeline Analysis report to focus upon each of the main targets of this cascade in turn. The major components of the cascade are described in more detail before outlining potential intervention strategies. The evidence for the role of this cascade in various diseases is then considered, highlighting the limited scope for modulating it with currently approved therapies. The report considers inhibition of PI3K, Akt, mTOR, and dual kinases, highlighting the inhibitors that are in development and assessing the current prospects for each approach.

The interest in therapeutically exploiting the PI3K cascade has seen a number of companies emerge that focus either exclusively or significantly on targeting one or more of the components in this cascade. Their successes in identifying promising inhibitors have also seen a number of high-value deals, both co-development agreements and acquisitions, demonstrating the perceived value of the targets that such companies are pursuing. Specialist key players are profiled, highlighting their distinct strategies, and also the considerable interest seen in deal-making in this area.

Finally, we consider the prospects of commercial success for agents that modulate the PI3K/Akt/mTOR cascade. As more detailed clinical data become available, it can be expected that the level of interest in this cascade, and expectations of what can be achieved by its modulation, will be increased.

Chapter 1
INTRODUCTION: 1.1. The PI3K/mTOR/Akt Signaling Cascade; 1.2. Activation and Key Kinases; 1.3. Report Structure
Chapter 2: THERAPEUTIC INTERVENTION; 2.1. PI3K; 2.2. Akt; 2.3. mTOR; 2.4. PDK1 and p70S6k; 2.5. Therapeutic Strategies
Chapter 3: THE PI3K/AKT CASCADE AND DISEASE; 3.1. Cancer; 3.2. Inflammation; 3.3. Other Indications; 3.4. Current Treatment Options
Chapter 4: PI3K INHIBITORS; 4.1. PI3K Inhibitors in Advanced Development; 4.2. Isoform-Selective Inhibitors; 4.3. Summary
Chapter 5: AKT INHIBITORS; 5.1. Akt Structure; 5.2. Akt and S6k Inhibitors in Clinical Development; 5.3. Summary
Chapter 6: mTOR INHIBITORS; 6.1. mTOR, TORC1, and TORC2; 6.2. Rapalogs; 6.3. Kinase Inhibitors; 6.4. Ridaforolimus; 6.5. OSI-027; 6.6. AZD-8055; 6.7. Summary
Chapter 7: DUAL INHIBITORS; 7.1. Dual Inhibitors in Development; 7.2. Phase I Compounds; 7.3. Phase II Compounds; 7.4. Summary
Chapter 8: KEY PLAYERS
Chapter 9: CURRENT OUTLOOK; Development Status of Inhibitors Targeting the PI3K Cascade; Commercial Prospects
Chapter 10: PI3K/AKT/mTOR CASCADE: EXPERT INTERVIEWS; Joseph R. Garlich, PhD, Co-Founder, Chief Scientific Officer, and Director, Semafore Pharmaceuticals, Westfield, IN; Christian Rommel, PhD, Chief Scientific Officer, Intellikine, La Jolla, CA; David Sherris, PhD, President and CEO, Paloma Pharmaceuticals, Jamaica Plain, MA; Prof. Steve Ward, Head of Pharmacology, Department of Pharmacy and Pharmacology, University of Bath, United Kingdom
References
Appendix A: RESULTS FROM INSIGHT PHARMA REPORTS' "PI3K CASCADE" SURVEY
SURVEY QUESTIONS: A1. How attractive a target would you rate this cascade compared to a) other exploited options, and b) other options under investigation?; A2. Compared to other protein kinase targets, how tractable do you rate each of these three kinases?; A3. The PI3K cascade offers multiple target options. For the treatment of cancer, which of these options do you feel offers greater promise?; A4. Isoform-selective PI3K inhibitors are an option for certain indications. On a scale of 0 (low) to 4 (high), please indicate how you perceive the attractiveness of each of the following options.; A5. With respect to clinical utility, do you see inhibitors of the PI3K cascade being positioned as monotherapy (for treating cancer) or in combination with other agents?; A6. Do you view the use of inhibitors of the PI3K cascade in combination with MEK inhibitors as the best option for combination therapy?; A7. On a scale of 0 (low) to 4 (high), please rate how you see the (potential) clinical usefulness of modulators of the PI3K cascade in targeting each of the following indications.
Appendix B: ACRONYMS
Company Index

The PI3K/Akt/mTOR Pathway

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