Abstract #SY32-2: CAL-101, a specific PI3K p110\#948; inhibitor for the treatment of hematological malignancies
2009
The class I phosphatidylinositol 3-kinases (PI3K) regulate a variety of cellular functions including motility, metabolism, proliferation, growth, and survival that play an important role in the etiology of cancer. Deregulation of the PI3K/Akt pathway by multiple mechanisms is one of the most frequently observed defects in human malignancies including those of hematological origin. Of the class IA PI3Ks (p110\#945;, p110\#946;, p110\#948;), p110\#948;\#8217;s expression is largely restricted to cells of hematopoietic origin. Mice deficient in p110\#948; have no gross abnormalities, are fertile, and live a normal lifespan without an increased susceptibility to infections. However, effects on intracellular signaling, proliferation, migration, or differentiation have been observed in both myeloid and lymphoid cells with the most pronounced effects on B cell development and survival. Therefore, selective targeting of PI3K signaling in hematological tumor cells could provide an effective treatment strategy while limiting potential undesirable effects of pan-inhibitors that broadly block PI3K signaling in all cells. Here, we report on the characterization of a novel p110\#948; specific inhibitor, CAL-101. This compound is a potent PI3K inhibitor with an IC 50 of 2 nM against the purified p110\#948; subunit and 65 nM cellular potency against p110\#948;-mediated basophil activation in whole blood. CAL-101 demonstrates 45-400 fold selectivity over the other class I PI3Kinases and no activity against class II and III PI3K family members or other PI3K-related proteins including mTOR and DNA-PK. Furthermore, a genome wide screen of >350 protein kinases did not detect inhibitory activity. To investigate the potential role of p110\#948; in hematologic tumors we screened a wide range of leukemia and lymphoma cell lines for p110 isoform expression and constitutive PI3K pathway activation. The expression of p110\#948; was observed in >90% of these cell lines that was in many cases accompanied by constitutive Akt phosphorylation. In this context, CAL-101 was able to reduce p-Akt levels and block additional downstream effectors such as p-p70S6K, p-GSK\#946;, and p-Bad in cells that represent a range of tumor types including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma and multiple myeloma (MM) among others. Further preclinical proof of concept has been provided through the analysis of primary tumor cells from patients with AML, chronic lymphocytic leukemia (CLL), ALL and MM. For each of these indications, all patient samples expressed a high level of p110\#948; protein with variable expression of the other isoforms and selective inhibition of p110\#948; by CAL-101 resulted in PI3K pathway inhibition and/or the induction cellular apoptosis. Interestingly, the protective effects of the tumor microenvironment or the addition of survival factors did not overcome the ability of CAL-101 to induce primary tumor cell killing. Our initial Phase 1 clinical study in normal human volunteers demonstrated good tolerability, high drug exposure and favorable steady-state pharmacokinetic properties with evidence of p110 delta inhibition. Taken together, these data support the on going Phase 1 clinical trial in patients with CLL, non-Hodgkins lymphomas and AML. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr SY32-2.
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