ONC212, alone or in synergistic conjunction with Navitoclax (ABT-263), promotes cancer cell apoptosis via unconventional mitochondrial-independent caspase-3 activation

Basu, Vishal; Shabnam,; Murghai, Yamini; Ali, Maqsood; Sahu, Swetangini; Verma, Bhupendra K.; Seervi, Mahendra

doi:10.1186/s12964-024-01817-1

Cell Commun Signal

2024

DOI: 10.1186/s12964-024-01817-1

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ONC212, alone or in synergistic conjunction with Navitoclax (ABT-263), promotes cancer cell apoptosis via unconventional mitochondrial-independent caspase-3 activation

Vishal Basu,

Shabnam,

Yamini Murghai

et al.

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2024

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Development of Novel Imipridones with Alkyne- and Triazole-Linked Warheads on the Tricyclic Skeleton, Showing Superior Ability to Eradicate PANC-1 and Fadu Cells Compared to ONC201

Czuczi,

Murányi,

Móra

et al. 2024

IJMS

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Our ongoing research focuses on the development of new imipridone derivatives. We aim to design compounds that can completely and selectively eradicate cancer cells after relatively short treatment. We have synthetized systematically designed novel hybrids and evaluated their antiproliferative activity against PANC-1 and Fadu cell lines. We have also conducted preliminary studies on the mechanism, including colony formation as well as dose–response tests in HEK293T wild-type (WT) and HEK293T CLPP−/− cells. Following gradual structural fine-tuning based on high throughput screening, we identified two imipridone hybrids as the most potent derivatives. Their unique substitution pattern includes N-methylated propargylamine and ferrocenyl/phenyltriazole moieties on the benzyl groups attached to opposite sides of the imipridone core. We found that the compounds with IC50 values similar to those of ONC201 completely eradicated cancer cells at about 4 μM, while ONC201 treatment at even higher concentrations left 30–50% of viable cells behind. Both compounds exerted equal activity in WT and CLPP−/− HEK293T cells, indicating a ClpP-independent mechanism. Further development is needed to improve the tumor selectivity of the two potent imipridone derivatives. By preserving tumor cytotoxicity, we aim to generate new drug candidates that evade resistance and can be applied in a sufficiently broad therapeutic window.

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Development of Novel Imipridones with Alkyne- and Triazole-Linked Warheads on the Tricyclic Skeleton, Showing Superior Ability to Eradicate PANC-1 and Fadu Cells Compared to ONC201

Czuczi,

Murányi,

Móra

et al. 2024

IJMS

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show abstract

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ONC212, alone or in synergistic conjunction with Navitoclax (ABT-263), promotes cancer cell apoptosis via unconventional mitochondrial-independent caspase-3 activation

Cited by 1 publication

References 68 publications

Development of Novel Imipridones with Alkyne- and Triazole-Linked Warheads on the Tricyclic Skeleton, Showing Superior Ability to Eradicate PANC-1 and Fadu Cells Compared to ONC201

Development of Novel Imipridones with Alkyne- and Triazole-Linked Warheads on the Tricyclic Skeleton, Showing Superior Ability to Eradicate PANC-1 and Fadu Cells Compared to ONC201

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