Targeting Thyrointegrin αvβ3 Using Fluorobenzyl Polyethylene Glycol Conjugated Tetraiodothyroacetic Acid (NP751) in Acute Myeloid Leukemia

Abstract

BackgroundAcute myeloid leukemia (AML) is associated with poor long-term survival, even with newer therapeutic agents. Here, we show the results of our preclinical study, in which we evaluated the efficacy of a new thyrointegrin αvβ3 antagonist, named fluorobenzyl polyethylene glycol conjugated tetraiodothyroacetic acid (fb-PMT).Methods and Resultsfb-PMT (NP751) is a potent αvβ3 antagonist of molecular weight of 2,478.9 Da. it represents a conjugate of tetraiodothyroacetic acid (tetrac) and monodisperse polyethylene glycol (PEG36), with a 4-fluorobenzyl group capping the other end of the PEG. fb-PMT effectively suppresses the malignant growth of human acute myeloid leukemia (AML) after successful engraftment in transgenic NSG-S xenograft mouse models of either established human AML cell line or primary AML cells. Daily treatment with fb-PMT (1–10 mg/kg body weight) subcutaneously (s.c.) for 3–4 weeks was associated with marked regression of leukemogenesis and extended survival in both models. The efficiency of the fb-PMT therapy was verified using in vivo imaging system (IVIS) imaging, flow cytometry, and histopathological examination to monitor the engraftment of leukemic cells in the bone marrow and other organs. fb-PMT therapy for 3–4 weeks at 3 and 10 mg/kg daily doses exhibited significant reduction (p < 0.0001) of leukemic cell burden of 74% and >95%, respectively. All fb-PMT-treated mice in the 10 mg/kg treatment arm successfully maintained remission after discontinuing the daily treatment. Comprehensive fb-PMT safety assessments demonstrated excellent safety and tolerability at multiple folds above the anticipated human therapeutic doses. Lastly, our genome-wide microarray screens demonstrated that fb-PMT works through the molecular interference mechanism with multiple signaling pathways contributing to growth and survival of leukemic cells.ConclusionOur preclinical findings of the potent anticancer activities of fb-PMT and its favorable safety profiles warrant its clinical investigation for the effective and safe management of AML.

Targeting integrins in drug‐resistant acute myeloid leukaemia

“…P‐bi‐TAT proves to be a hopeful therapeutic agent for most AML subtypes. The same group studied another αvβ3 antagonist, fluorobenzyl polyethylene glycol conjugated tetraiodothyroacetic acid (fb‐PMT or NP751) (Darwish et al, 2021). The fb‐PMT compound was observed to be safe and tolerated in xenograft mice, with stable remission after 3–4 weeks of treatment.…”

Preclinical assessment of drug–drug interaction of fb‐PMT, a novel anti‐cancer thyrointegrin αvβ3 antagonist

“…6 The pharmacodynamic and pharmacokinetic properties of PEG-TAT conjugated molecules are attributed to the optimized chemical structure of this drug-polymer conjugate. [7][8][9][10] Drug-drug interactions (DDIs) are problematic when a drug candidate enters into clinical applications because they may affect pharmacokinetic and pharmacodynamic properties of other pharmaceuticals administered at the same time. 11 Preclinical assessment of DDIs is, therefore, important to minimize potential adverse effects of drug candidates when they are used in the clinical setting.…”

“…We developed fb‐PMT as a targeted anticancer drug‐polymer conjugate with a high efficacy toward multiple cancers 6 . The pharmacodynamic and pharmacokinetic properties of PEG‐TAT conjugated molecules are attributed to the optimized chemical structure of this drug‐polymer conjugate 7–10 …”

“… 6 The pharmacodynamic and pharmacokinetic properties of PEG‐TAT conjugated molecules are attributed to the optimized chemical structure of this drug‐polymer conjugate. 7 , 8 , 9 , 10 …”

The power of heteronemin in cancers

“…Taking together, we presume that the integrin αvβ3 is the novel target in cancer cells that mediates the antitumor activity of heteronemin and we apply molecular modeling to define the interaction of heteronemin and integrin αvβ3. In addition, the published efficacy of the principal tetrac-containing lead candidate (fb-PMT) shows high integrin αvβ3 binding potency with an IC 50 of 0.23 nM against glioblastoma and acute myeloid leukemia [ 25 , 26 ]. The animal studies found no recurrence or relapse of xenografts with discontinuation of fb-PMT and cancer cells have been replaced by normal cells [ 25 ].…”