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An Orally Available Halothiazole Glycomimetic as a Cancer-Targeting Dual Galectin-1 and Galectin-3 Inhibitor
Fredrik R Zetterberg1, Kristoffer Peterson1, Ulf J Nilsson1,2
1Galecto Biotech AB, Sahlgrenska Science Park, Medicinaregatan 8 A, Gothenburg SE-413 46, Sweden.
Abstract:
Inhibition of several of the 10 hallmarks of cancer (Hanahan and Weinberg) would result in a broader and more durable treatment compared to current single or combination drug treatments. Galectin-1 and galectin-3 have been proposed to together be involved in all 10 hallmarks, suggesting that development of a combined galectin-1/3 inhibitor would be beneficial. Specificity toward galectin-1 or -3 can be modulated using different aryl moieties in 3-(aryl)triazolyl-galactopyranoside derivatives. By combining these findings, a new class of 3-(halothiazolyl)triazolyl derivatives with high affinity for both human galectin-1 and -3 were discovered and optimized with respect to SAR and in vitro ADME parameters, resulting in GB1841 (Kd galectin-1/-3 0.027/0.14 μM). Both selective and dual inhibition of galectin-1 and galectin-3 significantly reduces the growth of LL/2 lung cancer cells in a syngeneic mouse model, supporting further development of GB1841 as a dual inhibitor of galectin-1 and galectin-3.
Insights
Targeting galectins (galectin-1 and galectin-3) offers a novel cancer therapy approach. A new dual inhibitor, GB1841, effectively reduced lung cancer cell growth in preclinical studies.
Area of Science:
- Oncology
- Biochemistry
- Medicinal Chemistry
Background:
- The 10 hallmarks of cancer necessitate broader therapeutic strategies beyond current treatments.
- Galectins, specifically galectin-1 and galectin-3, are implicated in all cancer hallmarks.
- Targeting both galectin-1 and galectin-3 simultaneously presents a promising therapeutic avenue.
Purpose of the Study:
- To develop novel dual inhibitors of galectin-1 and galectin-3.
- To optimize compounds for high affinity and favorable in vitro ADME properties.
- To evaluate the efficacy of dual galectin inhibition in a preclinical cancer model.
Main Methods:
- Design and synthesis of 3-(halothiazolyl)triazolyl derivatives.
- Structure-activity relationship (SAR) studies and in vitro ADME profiling.
- In vivo evaluation of compound GB1841 in a syngeneic LL/2 lung cancer mouse model.
Main Results:
- Discovery and optimization of a new class of dual galectin-1/3 inhibitors.
- Compound GB1841 demonstrated high affinity for both galectin-1 (Kd 0.027 μM) and galectin-3 (Kd 0.14 μM).
- Both selective and dual inhibition significantly reduced LL/2 lung cancer cell growth in vivo.
Conclusions:
- Dual inhibition of galectin-1 and galectin-3 is a viable strategy for cancer treatment.
- GB1841 is a promising dual galectin inhibitor candidate for further preclinical development.
- Targeting galectins offers a potential approach to address multiple cancer hallmarks.
