New Inhibitor Targeting Signal Transducer and Activator of Transcription 5 (STAT5) Signaling in Myeloid Leukemias

Abstract

Signal transducers and activators of transcription 5 (STAT5s) are crucial effectors of tyrosine kinase oncogenes in myeloid leukemias. Inhibition of STAT5 would contribute to reducing the survival of leukemic cells and also tackling their chemoresistance. In a first screening experiment, we identified hit 13 as able to inhibit STAT5 phosphorylation and leukemic cell growth. The synthesis of 18 analogues of 13 allowed us to identify one compound, 17f, as having the most potent antileukemic effect. 17f inhibited the growth of acute and chronic myeloid leukemia cells and the phosphorylation and transcriptional activity of STAT5. Importantly, 17f had minimal effects on bone marrow stromal cells that play vital functions in the microenvironment of hematopoietic and leukemic cells. We also demonstrated that 17f inhibits STAT5 but not STAT3, AKT, or Erk1/2 phosphorylation. These results suggest that 17f might be a new lead molecule targeting STAT5 signaling in myeloid leukemias.

Direct Targeting Options for STAT3 and STAT5 in Cancer

“…Intracellular physiological concentrations of formaldehyde also emphasize the viability of this molecule as a STAT inhibitor and the utility of bio-catalytic Mannich reactions [105]. A study by Juen et al reported the optimization of the STAT5 inhibitor, Cpd17f (Figure 3v) [103]. Interestingly, the initial hit was originally intended for PPARα/γ inhibition, while the inhibition of STAT5 phosphorylation was an off-target effect [106].…”

Inhibitors Targeting STAT5 Signaling in Myeloid Leukemias: New Tetrahydroquinoline Derivatives with Improved Antileukemic Potential

“…This compound is composed of a 3‐pyridinyl substituted 4,4‐dimethyl‐1,2,3,4‐tetrahydroquinoline (THQ) and indole rings, linked by an ethoxy chain attached by carbon C‐5 of the indole and nitrogen N‐1 of the THQ (Figure 1). We showed that 17 f suppressed P−Y‐STAT5 and growth of CML and AML cells [41] . We also demonstrated that 17 f sensitizes leukemic cells that acquired resistance to IM or Ara‐C [42] …”

“…Compounds 8 b and 8 c subsequently yielded 9 b and 9 c after Suzuki coupling using 2‐bromopyridine [43,44] . Concerning compound 9 b , this optimized procedure allowed us to improve the yield from 24 to 60 % in two steps [41] . Though, concerning pinacol boronate ester 8 a , coupling was not observed, surely due to steric hindrance between methyl groups of both pinacol boronate and THQ.…”

“…This synthetic route, setting good yields, has been extended to synthesize a series of new analogs using the brominated THQ and indole rings as starting materials with the linking strategy as described previously (Scheme 1). [41] To obtain these analogs series, we needed to synthetize the brominated key intermediates 4,4-dimethyl-1,2,3,4-tetrahydroquinoline 6, with bromine on positions 5, 7 and 8. From 2bromoaniline, we performed the same method used in Juen et al work with an acylation followed by a Friedel-Crafts alkylation to get lactam 2 d. [41] From 3-bromoaniline, we obtained as expected both lactam brominated on positions 5 and 7, and isolated each isomer by purification, respectively 2 a and 2 c. Each lactam was then reduced to the corresponding brominated THQ 3 a,c,d.…”

“…We showed that 17 f suppressed PÀ Y-STAT5 and growth of CML and AML cells. [41] We also demonstrated that 17 f sensitizes leukemic cells that acquired resistance to IM or Ara-C. [42] In order to improve the antileukemic potential of 17 f, we synthesized 10 new analogs with modifications around the tetrahydroquinoline (THQ) ring and analyzed their impacts on CML and AML cell growth. Among these analogs, two compounds, 7 a and 7 a', containing respectively a 3-and 4pyridinyl moiety in position 5 on the THQ ring, showed similar or higher growth inhibitory effects when compared to 17 f. We also demonstrated that 7 a and 7 a' were more effective than 17 f in blocking PÀ Y-STAT5 expression and activity.…”