12:00 AM
May 24, 2012
 |  BC Innovations  |  Targets & Mechanisms

Getting selective for gamma

Cellzome AG and Exelixis Inc. have independently designed the first highly selective inhibitors of the g-isoform of phosphoinositide 3-kinase.1,2 Exelixis plans to out-license its inhibitors, whereas last week's acquisition of Cellzome by GlaxoSmithKline plc gives the pharma a new class of compounds for inflammatory and autoimmune diseases.

Phosphoinositide 3-kinase (PI3K) plays a central role in signaling pathways that contribute to cell growth, proliferation, motility and survival. The kinase occurs in four isoforms. The a- and b-isoforms are expressed in many tissues and cell types, and the g- and d-isoforms are expressed in immune cells.

Aberrant activation of PI3Kα and PI3Kb is a key driver of many solid cancers, whereas activation of PI3Kg and PI3Kd can lead to hematological malignancies and inflammatory diseases.

For the past decade, the challenge has been to design PI3K inhibitors that selectively hit the isoform implicated in a given disease while sparing the function of the other isoforms. That has generally required chemists to optimize inhibitors that are 10-1,000 times more selective for one isoform over the others.3

Selective inhibitors of PI3Ka and PI3Kd have moved into the clinic, and inhibitors of PI3Kb are in preclinical testing ( "PI3Kg and PI3Kd inhibitor pipeline" Table 1, "PI3Kg and PI3Kd inhibitor pipeline"). Inhibiting PI3Kg has been more difficult.

Genetic data from a variety of animal models suggest selectively inhibiting PI3Kg could have a broad anti-inflammatory effect with potential utility in a range of diseases,4 including rheumatoid arthritis (RA),5 atherosclerosis6 and diabetes.7,8 Highly selective inhibition of PI3Kg also should avoid the cardiotoxicity that has been associated with some PI3K inhibitors in mice that antagonize the PI3Ka isoform (see Box 1, "Heartless PI3K inhibition").

Chemical scaffolds that work for the other three isoforms "often fail to potently inhibit PI3Kg," Christian Rommel told SciBX. "The ATP-binding pocket of PI3Kg is structurally distinct [from the other isoforms] and is more tight and narrow as well as less flexible."

Rommel is the former CSO of Intellikine Inc., which was acquired by Takeda Pharmaceutical Co. Ltd. this year for $190 million up front and up to $120 million in milestones. While at Intellikine, Rommel oversaw the development of INK1117, a PI3Ka-selective PI3K inhibitor that is in Phase I testing to treat solid tumors, and IPI-145, a dual inhibitor of PI3Kg and PI3Kd that is in Phase I testing to treat hematological malignancies.

Compared with dual inhibition of PI3Kg and PI3Kd, inhibiting only PI3Kg "is thought to be more suitable for myeloid-triggered inflammatory processes implicated in atherosclerosis and certain forms of metabolic disorders," said Rommel.

Going native

Cellzome researchers reasoned they might have a better chance of identifying a PI3Kg-selective PI3K inhibitor by using initial compound screens in whole-cell extracts rather than in panels of purified recombinant kinases.

The goal was to test the activity of inhibitors in a setting that mimics physiology, VP of Research Operations Gitte Neubauer told SciBX. "The targets are full length, post-translationally modified, and their interactions with other proteins are largely preserved," she said.

"There has been a growing realization that recombinant protein kinases, which are often truncated and/or fusion proteins, do not exhibit the same activity...

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