Abstract

Macrophages are involved in a plethora of physiological and
pathophysiological processes, including in cancer. Tumour-associated
macrophages are known to contribute to the malignancy of multiple cancers by
generating an immunosuppressive environment, whereas M1 macrophages promote
anti-tumour activity.

PI3K has recently been shown to play an important role in
macrophage polarization, making the enzyme an attractive target for anti-cancer
therapies (Kaneda et al, 2016). However, PI3K is ubiquitously expressed, including in
T-cells, and a global inhibition may lead to both counter-active
immune and adverse side effects.

Macrophage Pharma Limited have developed the Esterase
Sensitive Motif^TM (ESM^TM) technology which enables the
selective delivery of small molecule inhibitors to monocytes and macrophages.

Here we will present the preliminary
characterization of novel PI3K inhibitors, derived
using the ESM^TM technology platform, which selectively target
PI3K expressed in monocytes and macrophages while sparing other (immune)
cells.

We will present our results of compound profiling employing
various techniques including mass spectrometry, Western blotting, and AlphaLISA
technology.

We will demonstrate the selective accumulation of ESM^TM-targeted
inhibitors to monocytes over T cells, resulting in a significantly increased
potency of compounds in monocytes and prolonged cellular activity, even after
washout, demonstrating the benefits and potential of the ESM^TM technology.