Abstract 891: A novel quinazolin-4(3H)-one/Schiff base hybrid phosphodiesterase 4 inhibitor as a potential therapeutic agent for leukemia

Abstract Cyclic adenosine monophosphate (cAMP) is a secondary messenger that regulates cell proliferation, differentiation, and apoptosis. Phosphodiesterases (PDEs) are enzymes that catabolize cyclic nucleotides to relay cellular signals. Among them, PDE4 is a cAMP-specific PDE isozyme family and several PDE4 inhibitors have been developed to treat a diverse group of diseases, such as asthma and chronic obstructive pulmonary disease. Although PDE4 inhibitors have been demonstrated to induce cell death in solid tumors, their therapeutic potential in treatment of hematopoietic malignancies has not been well studied. Our analysis on the expression pattern of PDE family demonstrated that PDE4B is abundantly expressed in blood cancers compared to other solid tumors, implicating PDE4 as a potential therapeutic target for leukemia. N-acylhydrazone and nitraquazone are potent PDE inhibitors that are structurally unrelated to rolipram, a prototypical PDE4 inhibitor. To develop novel PDE4 inhibitors with increased scaffold rigidity, we hybridized N-acylhydrazone with Nitraquazone, and designed a series of quinazolin-4(3H)-one/schiff base hybrid compounds. Among those, compound 23 (CPD23) showed the best activity in PDE4B inhibition, and was selected for further studies. Our results showed that CPD23 treatment leads to growth inhibition and cell cycle arrest of several human leukemia cell lines. Since cAMP is a well-studied secondary messenger for megakaryopoesis and apoptosis, we continued to elucidate CPD23's mechanism of action in several megakaryoblastic leukemia cell lines. While other well-known PDE4 inhibitors, such as rolipram, did not show any effect in cell viability, CPD23 significantly decreases the viability of megakaryoblastic cell lines. Further studies on molecular actions revealed that CPD23 caused double-stranded DNA breaks, which was detected by increased ϒH2AX levels. Quantitative RT-PCR experiments also demonstrated that CPD23 induces transcriptional activation of megakaryocytic differentiation markers, such as CD61, in selective cell lines. Taken together, our study shows that CPD23, synthesized as a quinazolin-4(3H)-one/schiff base hybrid PDE4 inhibitor, decreases proliferation, induces double-stranded DNA breaks, and differentiation in megakaryoblastic leukemia cell lines. Further studies will enhance our knowledge on detailed molecular actions of CPD23 and its therapeutic value for leukemia. Citation Format: Alexander Richard, Hamdy M. Abdel-Rahman, Jung Hyun Kim, Lana Vukadin, Gary A. Piazza, Eun-Young E. Ahn. A novel quinazolin-4(3H)-one/Schiff base hybrid phosphodiesterase 4 inhibitor as a potential therapeutic agent for leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 891.