Design, synthesis and biological evaluation of tyrosine derivatives as Mcl-1 inhibitors

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Oncology

Background:

• Upregulation of myeloid cell leukemia-1 (Mcl-1) protein is linked to cancer development and poor patient outcomes.
• Mcl-1 inhibitors represent a promising therapeutic approach for cancer treatment.

Purpose of the Study:

• To design and synthesize novel tyrosine derivatives as potential Mcl-1 inhibitors.
• To evaluate the binding affinity, selectivity, and anti-cancer activity of these derivatives.

Main Methods:

• Chemical synthesis of tyrosine derivatives.
• In vitro assays to determine binding affinity (K_i) to Mcl-1.
• Molecular docking and fragment-centric topographical mapping (FCTM) for selectivity analysis.
• Antiproliferative assays and apoptosis induction studies in cancer cell lines.

Main Results:

• Compounds 5g, 6l, and 6c demonstrated high binding affinity to Mcl-1 with K_i values in the sub-micromolar range.
• Compound 6l exhibited potent Mcl-1 inhibition with notable selectivity over Bcl-2 and Bcl-xL.
• Compounds 5g, 6l, and 6c displayed significant antiproliferative effects and induced apoptosis in KM3 and HepG2 cells.

Conclusions:

• The novel tyrosine derivatives are effective Mcl-1 inhibitors.
• Compound 6l shows promising selectivity and potency for further cancer therapeutic development.
• These findings support the potential of targeting Mcl-1 for cancer treatment.