Design, Synthesis and Biological Evaluation of A Boron Containing Retinoid As a Novel Therapeutic Agent for Acute Promyelocytic Leukemia

Cure rates of acute leukemia remain poor emphasizing the need to for novel therapies. All trans retinoic acid (ATRA) is an effective therapeutic agent in a subtype of acute myeloid leukemia and relieves transcriptional repression induced by the PML-RAR oncoprotein by binding to the retinoic acid receptor. Even though ATRA is effective, the treatment course is characterized by a high rate of toxicity and ATRA resistance is seen in some cases of acute promyelocytic leukemia. In an attempt to improve outcomes, we devised a methodology for creation of boronic acid and other newer retinoic acid analogues. Our lead compound, MA-21 was generated by replacing the terminal carboxyl group of ATRA with a boronic ester using Wittig reactions. Computation modeling revealed that MA-21 can fit in the RARa pocket and can form increased covalent bonding with cysteine residues within the receptor. As opposed to other synthetic retinoids, the addition of a boron atom resulted in significantly enhanced cytotoxicity in leukemic cell lines, even those that were resistant to ATRA. MA-21 at 1uM dose led to significant reduction in proliferation of ATRA sensitive NB4 APL cell line (1.8 fold decrease after 96hrs, p= 0.028) as well as in ATRA resistant cell lines NB4.007/6 (3.3 fold decrease after 72hrs and 2.1 decrease after 96hrs, p values of 0.018 and 0.046) and NB4.306 (2.6 fold decrease after 96hrs, p= 0.032). MA-21 was able to induce these effects by inducing significant G2/M cell cycle arrest and not by increased apoptosis or cellular differentiation. Cell cycle was assessed by Flow Cytometry after 96hrs of incubation and showed a significant increase in G2/M percentage in the ATRA sensitive and resistant cell lines compared to DMSO (NB4 cell line- 1.35 fold increase, p= 0.035; NB4.007/6- 1.35 fold increase, p= 0.015 and NB4.306- 2 fold increase, p= 0.023). Thus, we demonstrate novel synthetic methodology to synthesize boron containing novel retinoids and demonstrate the potential of these compounds as therapeutic agents in resistant leukemias.