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12:00 AM
Feb 27, 2012
 |  BioCentury  |  Product Development

Take your PI(3)K

What pharma's PI3K land grab means for cancer, inflammationIntellikine's PI3K platform reaches back to the chemistry lab at UCSF

Questions remain about the optimal selectivity profiles for PI3K inhibitors, but big biopharmas are already making their bets. The shift from interesting science to investable compounds - about two decades in the making - hinged on marrying discoveries in PI3K biology to the ability of medicinal chemists to tweak the relative selectivity compounds for kinase isoforms that are implicated in a host of cancers, inflammatory diseases and respiratory disorders.

Few of the inhibitors of phosphoinositide 3-kinase (PI3K) now in the clinic, whose selectivity profiles have been disclosed, are uniquely selective for the disease-related isoform of interest. Indeed, even next-generation compounds generally show some activity against all isoforms, and in some cases even show equal activity against two or three isoforms.

Some companies say they want inhibitors that are orders of magnitude more selective for one isoform over other isoforms, while others want a compound that hits the targeted isoform with very high potency despite showing similar potency at other isoforms.

In either case, the early data have been promising enough to spur a spate of M&A and licensing deals.

The $190 million takeout of Intellikine Inc. by Takeda Pharmaceuticals Co. Ltd. in January was the third deal in a year aimed at getting access to next-generation isoform-selective PI3K inhibitors. The deal includes an inhibitor of the PI3K alpha isoform, a dual inhibitor of the gamma/delta isoforms and a selective inhibitor of the mTOR complex, which sits downstream of PI3K.

The other two were in April 2011, when Gilead Sciences Inc. acquired Calistoga Pharmaceuticals Inc., followed by Merck & Co. Inc. partnering with Exelixis Inc. Both companies' programs target the delta isoform.

The first deal actually came in 2008, two years after the first publication of an isoform-selective inhibitor, when Roche acquired Piramed Ltd. for its alpha-selective PI3K inhibitor (see "PI3K Deal Flow," A14).

At least three small biotechs have unpartnered PI3K programs (see " PI3K Pipeline," A10).

A tale of 4 targets

As the most upstream component of an established cancer pathway, PI3K has generated considerable attention as a potential target since the late 1980s. But the ubiquity of the pathway in healthy tissues meant development of PI3K inhibitors lagged behind inhibitors of other proteins in the pathway like mTOR.

Indeed, first-generation PI3K inhibitors developed in the mid-1990s never entered the clinic for a variety of reasons, including poor bioavailability and toxicity.

In the late '90s, research revealed PI3K occurs in four isoforms that have varying tissue distributions. The alpha and beta isoforms are expressed in almost all tissues and cell types, whereas the gamma and delta isoforms are expressed only in immune cells.

Moreover, in solid cancers it is primarily the alpha isoform that is activated, while in hematological malignancies the delta isoform is activated.

Those findings helped explain the problems with first-generation inhibitors, which hit all four isoforms with equal potency, and suggested the need for isoform-selective inhibitors.

The time was then ripe for medicinal chemists to try their hand at rationally designing isoform-selective inhibitors, using high resolution X-ray crystal structures of PI3K (see "Intellikine's Story," A15).

Five years later, the first isoform-selective compounds began appearing in the literature.

In 2006, Calistoga researchers published on a delta-selective PI3K inhibitor in Oncogene. In 2008, Piramed researchers published on an alpha-selective inhibitor in the Journal of Medicinal Chemistry. Also in 2008, Novartis AG researchers published on a dual PI3K alpha/mTOR inhibitor in Molecular Cancer Therapeutics.

However, there is no agreed-upon definition of what constitutes isoform selectivity, and different labs have used a range of in vitro and cell-based assays to measure it. As a result, comparing the selectivity profiles of the inhibitors is not straightforward.

Based on those assays, the majority of isoform-selective inhibitors in the clinic appear to inhibit two or three PI3K isoforms with similar potency. Moreover, some of the so-called alpha-selective inhibitors appear to inhibit the delta isoform more potently than compounds that are intended to be delta-selective.

Intellikine and Karus Therapeutics Ltd. declined to comment on what the ideal selectivity profile might be for a giving inhibitor in a given indication. However, Pathway Therapeutics Inc. did say it defines a selective inhibitor as one that shows at least 100 times higher selectivity for one isoform over others.

In any event, Paul Workman of Cancer Research UK predicts the selectivity preferences will be established in the clinic.

"The pros and cons of different PI3K isoform-selectivity profiles will ultimately emerge from data on the therapeutic versus side effect properties," he wrote in Nature Chemical Biology in 2010.

Year of the delta

In their deals, Gilead and Merck both picked compounds designed to be delta-selective.

The expression of PI3K delta is generally restricted to hematopoietic cell types. In inflammation, the delta isoform has been implicated in B and T cell antigen receptor signaling, neutrophil migration and allergen-induced mast cell degranulation.

In cancer, PI3K delta plays an essential role in regulating cell proliferation and survival in chronic lymphocytic leukemia (CLL) and acute myelogenous leukemia (AML).

Gilead's acquisition of Calistoga for $375 million in cash plus up to $225 million in milestones gave the big biotech the most advanced delta-specific PI3K inhibitor. Calistoga's CAL-101 entered the clinic to treat hematological malignancies in 2008 and also is one of the few next-generation compounds whose selectivity clearly...

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