Discovery of a Novel Selective PAK1/HDAC6/HDAC10 Inhibitor ZMF-25 that Induces Mitochondrial Metabolic Breakdown and
Jin Zhang1, Xiaoling Cheng1,2, Gang Chen1,2
1School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China.
Abstract:
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, and addressing its intrinsic heterogeneity has emerged as a valuable avenue for novel clinical treatment strategy. Here, we put forward an innovative strategy for TNBC treatment by simultaneously suppressing both p21-activated kinase 1 (PAK1) and histone deacetylase (HDAC) class IIb (HDAC6/10). A series of pyrido [2,3-d]pyrimidin-7(8H)-one moiety derivatives was successfully designed and synthesized to target PAK1/HDAC6/HDAC10 by utilizing structure-based screening and pharmacophore integration. ZMF-25 demonstrates marked inhibitory activity against PAK1, HDAC6, and HDAC10 with respective IC50 values of 33, 64, and 41 nM, remarkable selectivity over HDACs and PAKs, as well as prominent antiproliferative efficiency in MDA-MB-231 cells. Additionally, ZMF-25 effectively suppresses TNBC proliferation and migration by inhibiting PAK1/HDAC6/HDAC10. Moreover, it was found to impair glycolysis and trigger reactive oxygen species generation, resulting in autophagy-related cell death by inhibiting the AKT/mTOR/ULK1 signaling. Furthermore, ZMF-25 exhibits remarkable therapeutic potential with no obvious toxicity in vivo and good pharmacokinetics. In summary, these observations indicate that ZMF-25 is a novel and potent triple-targeting PAK1/HDAC6/HDAC10 inhibitor, which is expected to provide a novel and effective strategy for TNBC treatment.
Insights
A novel compound, ZMF-25, effectively targets p21-activated kinase 1 (PAK1) and histone deacetylase (HDAC) 6/10. This triple-targeting approach shows promise for treating aggressive triple-negative breast cancer (TNBC) with minimal toxicity.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options.
- Addressing TNBC heterogeneity is crucial for developing new therapeutic strategies.
- Simultaneous targeting of key signaling pathways offers a promising approach for TNBC treatment.
Purpose of the Study:
- To design and synthesize novel pyrido[2,3-d]pyrimidin-7(8H)-one derivatives as inhibitors of p21-activated kinase 1 (PAK1) and histone deacetylase (HDAC) class IIb (HDAC6/10).
- To evaluate the efficacy of these compounds in inhibiting TNBC proliferation, migration, and related signaling pathways.
- To assess the in vivo therapeutic potential and pharmacokinetic profile of the lead compound.
Main Methods:
- Structure-based screening and pharmacophore integration were used to design novel compounds.
- In vitro assays were performed to determine IC50 values and selectivity for PAK1, HDAC6, and HDAC10.
- Antiproliferative and anti-migration assays were conducted using MDA-MB-231 TNBC cells.
- Mechanism of action studies investigated effects on glycolysis, reactive oxygen species (ROS) generation, and AKT/mTOR/ULK1 signaling.
- In vivo studies evaluated therapeutic efficacy and toxicity in a preclinical setting.
Main Results:
- ZMF-25 demonstrated potent inhibition of PAK1, HDAC6, and HDAC10 with nanomolar IC50 values.
- The compound exhibited remarkable selectivity for the targeted enzymes over other HDACs and PAKs.
- ZMF-25 significantly suppressed proliferation and migration of MDA-MB-231 cells.
- The inhibitor impaired glycolysis, induced ROS generation, and triggered autophagy-related cell death via AKT/mTOR/ULK1 pathway inhibition.
- ZMF-25 showed significant therapeutic potential in vivo with no obvious toxicity and favorable pharmacokinetics.
Conclusions:
- ZMF-25 is a novel and potent triple-targeting inhibitor of PAK1, HDAC6, and HDAC10.
- This compound represents a promising new therapeutic strategy for triple-negative breast cancer.
- The dual inhibition of PAK1 and HDAC6/10 offers a unique approach to combat TNBC heterogeneity and progression.
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