Targeting BPTF Sensitizes Pancreatic Ductal Adenocarcinoma to Chemotherapy by Repressing ABC-Transporters and Impairing Multidrug Resistance (MDR)

Velasco, Raúl Muñoz; Sánchez, Paula Jiménez; García, Ana García; Martínez-Illescas, Raquel Blanco; Senovilla, Ángela Pastor; Yagüe, Marian Lozano; Trento, Alfonsina; García-Martín, Rosa; Navarro, Diego; Sáinz, Bruno; Peralto, J.L. Rodríguez; Lobo, Víctor J. Sánchez-Arévalo

doi:10.3390/cancers14061518

Cited by 5 publications

(9 citation statements)

References 44 publications

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“…These studies also highlight the benefit of using multiple scaffolds with different selectivity profiles for initial studies of previously undegraded proteins. Areas for future investigation include the recently demonstrated role of CECR2 in breast cancer metathesis and pancreatic cancer driven by high levels of BPTF and MYC …”

Section: Discussionmentioning

confidence: 99%

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Design of Class I/IV Bromodomain-Targeting Degraders for Chromatin Remodeling Complexes

Zahid

Costello

et al. 2023

ACS Chem. Biol.

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Targeted protein degradation is an emerging technology that can be used for modulating the activity of epigenetic protein targets. Among bromodomain-containing proteins, a number of degraders for the BET family have been developed, while non-BET bromodomains remain underexplored. Several of these proteins are subunits in chromatin remodeling complexes often associated with oncogenic roles. Here, we describe the design of class I (BPTF and CECR2) and IV (BRD9) bromodomain-targeting degraders based on two scaffolds derived from pyridazinone and pyrimidine-based heterocycles. We evaluate various exit vectors and linkers to identify analogues that demonstrate selectivity within these families. We further use an in-cell NanoBRET assay to demonstrate that these heterobifunctional molecules are cell-permeable, form ternary complexes, and can degrade nanoluciferase–bromodomain fusions. As a first example of a CECR2 degrader, we observe that our pyrimidine-based analogues degrade endogenous CECR2 while showing a smaller effect on BPTF levels. The pyridazinone-based compounds did not degrade BPTF when observed through Western blotting, further supporting a more challenging target for degradation and a goal for future optimization.

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Section: Discussionmentioning

confidence: 99%

“…Areas for future investigation include the recently demonstrated role of CECR2 in breast cancer metathesis 24 and pancreatic cancer driven by high levels of BPTF and MYC. 40 ■ EXPERIMENTAL SECTION Materials and Methods. All commercially available reagents were used without further purification.…”

Section: ■ Conclusionmentioning

confidence: 99%

Design of Class I/IV Bromodomain-Targeting Degraders for Chromatin Remodeling Complexes

Zahid

Costello

et al. 2023

ACS Chem. Biol.

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“…These include the recently demonstrated role of CECR2 in breast cancer metathesis 23 and pancreatic cancer driven by high levels of BPTF and MYC. 36 Further optimization of our first-generation degraders and a more extensive study of various model cell lines will be evaluated for targeting these important nucleosome remodeling complexes. General procedure A for the synthesis of intermediates 13-16.…”

Section: Discussionmentioning

confidence: 99%

“…These tool compounds provide a starting point to evaluate the effects of targeted protein degradation in cancer models. These include the recently demonstrated role of CECR2 in breast cancer metathesis23 and pancreatic cancer driven by high levels of BPTF and MYC 36. Further optimization of our first-generation degraders and a more extensive study of various model cell lines will be evaluated for targeting these important nucleosome remodeling complexes.…”

mentioning

confidence: 99%

Design of Class I/IV Bromodomain-Targeting Degraders for Chromatin Remodeling Complexes

Zahid

Costello

Kimbrough

et al. 2022

Preprint

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Targeted protein degradation is an emerging technology that can be used for modulating the activity of epigenetic protein targets. Among bromodomain-containing proteins, a number of degraders for the BET family have been developed while non-BET bromodomains remain underexplored. Several of these proteins are subunits in chromatin remodeling complexes often associated with oncogenic roles. Here we describe the design of class I (BPTF and CECR2) and IV (BRD9) bromo-domain-targeting degraders based on two scaffolds derived from pyridazinone and pyrimidine-based heterocycles. We evalu-ate various exit vectors and linkers to identify analogues that demonstrate selectivity within these families. We further use an in-cell NanoBRET assay to demonstrate that these heterobifunctional molecules are cell-permeable, form ternary complexes, and can degrade nanoluciferase-bromodomain fusions. Finally, as a first example of a CECR2 degrader, we observe that our pyrimidine-based analogues degrade endogenous CECR2, while showing a smaller effect on BPTF levels. The pyridazinone-based compounds did not degrade BPTF when observed through western blotting, supporting a more challenging target for degradation and a goal for future optimization

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“…MYC interacts with BPTF to induce MDR in cancer cells through upregulation of ABC transporters [ 376 ]. BPTF is a cofactor that alters chromatin structure to increase transcription activation and recruitment of c-MYC to ABC-transporter promoters, elevating their expression and contributing to gemcitabine (drug) resistance [ 377 , 378 ].…”

Section: Functional Roles Of Myc In Cancer Cellsmentioning

confidence: 99%

MYC Oncogene: A Druggable Target for Treating Cancers with Natural Products

Chan,

Zhang,

et al. 2024

Aging and disease

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Various diseases, including cancers, age-associated disorders, and acute liver failure, have been linked to the oncogene, MYC . Animal testing and clinical trials have shown that sustained tumor volume reduction can be achieved when MYC is inactivated, and different combinations of therapeutic agents including MYC inhibitors are currently being developed. In this review, we first provide a summary of the multiple biological functions of the MYC oncoprotein in cancer treatment, highlighting that the equilibrium points of the MYC/MAX, MIZ1/MYC/MAX, and MAD (MNT)/MAX complexes have further potential in cancer treatment that could be used to restrain MYC oncogene expression and its functions in tumorigenesis. We also discuss the multifunctional capacity of MYC in various cellular cancer processes, including its influences on immune response, metabolism, cell cycle, apoptosis, autophagy, pyroptosis, metastasis, angiogenesis, multidrug resistance, and intestinal flora. Moreover, we summarize the MYC therapy patent landscape and emphasize the potential of MYC as a druggable target, using herbal medicine modulators. Finally, we describe pending challenges and future perspectives in biomedical research, involving the development of therapeutic approaches to modulate MYC or its targeted genes. Patients with cancers driven by MYC signaling may benefit from therapies targeting these pathways, which could delay cancerous growth and recover antitumor immune responses.

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Targeting BPTF Sensitizes Pancreatic Ductal Adenocarcinoma to Chemotherapy by Repressing ABC-Transporters and Impairing Multidrug Resistance (MDR)

Cited by 5 publications

References 44 publications

Design of Class I/IV Bromodomain-Targeting Degraders for Chromatin Remodeling Complexes

Design of Class I/IV Bromodomain-Targeting Degraders for Chromatin Remodeling Complexes

Design of Class I/IV Bromodomain-Targeting Degraders for Chromatin Remodeling Complexes

MYC Oncogene: A Druggable Target for Treating Cancers with Natural Products

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