Conjugation of Palbociclib with MHI-148 Has an Increased Cytotoxic Effect for Breast Cancer Cells and an Altered Mechanism of Action

Abstract

The CDK4/6 inhibitor palbociclib, combined with endocrine therapy, has been shown to be effective in postmenopausal women with estrogen receptor-positive, HER2-negative advanced or metastatic breast cancer. However, palbociclib is not as effective in the highly aggressive, triple-negative breast cancer that lacks sensitivity to chemotherapy or endocrine therapy. We hypothesized that conjugation of the near-infrared dye MHI-148 with palbociclib can produce a potential theranostic in triple-negative, as well as estrogen receptor-positive, breast cancer cells. In our study, the conjugate was found to have enhanced activity in all mammalian cell lines tested in vitro. However, the conjugate was cytotoxic and did not induce G1 cell cycle arrest in breast cancer cells, suggesting its mechanism of action differs from the parent compound palbociclib. The study highlights the importance of investigating the mechanism of conjugates of near-infrared dyes to therapeutic compounds, as conjugation can potentially result in a change of mechanism or target, with an enhanced cytotoxic effect in this case.

The search for CDK4/6 inhibitor biomarkers has been hampered by inappropriate proliferation assays

“…This implies that the only partially reliable largescale screen to date is GDSC1, which used a DNA-based endpoint in the adherent cell types, but a metabolic endpoint in the suspension cell types 3 . In addition, a number of smaller scale screens have used either a DNA-based endpoints or cell counts to determine palbociclib sensitivity [19][20][21][22][23][24][25][26][27][28] , which would both accurately determine arrest efficiency irrespective of cell size. We therefore combined data from these small screens with the GDSC1 adherent cell data and used DepMap to analyse codependencies (See Supplementary Table 1 for full list of cells lines and associated palbociclib IC50 data).…”

“…A literature search identified 11 studies that used DNA-based or cell count-based proliferation assay to determine palbociclib IC50s 3,[19][20][21][22][23][24][25][26][27][28] . The data from these studies was combined, and duplicate cell lines data was removed.…”

Site-specific albumin tagging with chloride-containing near-infrared cyanine dyes: molecular engineering, mechanism, and imaging applications

“…The binding of Cl-containing cyanine dyes to albumin allows for the storage of albumin conjugates in cells for a prolonged period, thus making the utilization of dye side chains for drug delivery as an effective approach. 92,99 The combination of dasatinib (a Lyn and Src kinase inhibitor) and MHI-148 to form the conjugate KI-Cy has proven to be successful, exhibiting superior potency against the U87 glioblastoma cell line (Fig. 9).…”

Multifunctional Nanoplatform for NIR-II Imaging-Guided Synergistic Oncotherapy

“…Small molecule probes (e.g., certain peptides and inhibitors) have unique advantages over macromolecular polymers in tumor therapy due to their convenient synthesis methods, simple chemical modifications, and strong stability [69,70]. Tao et al [33] synthesized fluorescent probes with NIR-I emission and applied them to tissue and tumor model imaging.…”