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1.
Proc Natl Acad Sci U S A ; 121(15): e2322563121, 2024 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-38557192

RESUMEN

Mammalian switch/sucrose nonfermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, an orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. Importantly, AU-24118 exhibited favorable pharmacokinetic profiles in preclinical analyses in mice and rats, and further toxicity testing in mice showed a favorable safety profile. As acquired resistance is common with targeted cancer therapeutics, experiments were designed to explore potential mechanisms of resistance that may arise with long-term mSWI/SNF ATPase PROTAC treatment. Prostate cancer cell lines exposed to long-term treatment with high doses of a mSWI/SNF ATPase degrader developed SMARCA4 bromodomain mutations and ABCB1 (ATP binding cassette subfamily B member 1) overexpression as acquired mechanisms of resistance. Intriguingly, while SMARCA4 mutations provided specific resistance to mSWI/SNF degraders, ABCB1 overexpression provided broader resistance to other potent PROTAC degraders targeting bromodomain-containing protein 4 and AR. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise.


Asunto(s)
Adenosina Trifosfatasas , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Ratas , Ratones , Animales , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Línea Celular , Cromatina , Mamíferos/genética , Antagonistas de Receptores Androgénicos , ADN Helicasas/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética
2.
bioRxiv ; 2024 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-38464081

RESUMEN

Mammalian switch/sucrose non-fermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, a first-in-class, orally bioavailable proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. Importantly, AU-24118 exhibited favorable pharmacokinetic profiles in preclinical analyses in mice and rats, and further toxicity testing in mice showed a favorable safety profile. As acquired resistance is common with targeted cancer therapeutics, experiments were designed to explore potential mechanisms of resistance that may arise with long-term mSWI/SNF ATPase PROTAC treatment. Prostate cancer cell lines exposed to long-term treatment with high doses of a mSWI/SNF ATPase degrader developed SMARCA4 bromodomain mutations and ABCB1 overexpression as acquired mechanisms of resistance. Intriguingly, while SMARCA4 mutations provided specific resistance to mSWI/SNF degraders, ABCB1 overexpression provided broader resistance to other potent PROTAC degraders targeting bromodomain-containing protein 4 (BRD4) and AR. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise.

3.
Mol Cancer Ther ; 21(6): 890-902, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35642432

RESUMEN

Nearly 30% of patients with relapsed breast cancer present activating mutations in estrogen receptor alpha (ERα) that confer partial resistance to existing endocrine-based therapies. We previously reported the development of H3B-5942, a covalent ERα antagonist that engages cysteine-530 (C530) to achieve potency against both wild-type (ERαWT) and mutant ERα (ERαMUT). Anticipating that the emergence of C530 mutations could promote resistance to H3B-5942, we applied structure-based drug design to improve the potency of the core scaffold to further enhance the antagonistic activity in addition to covalent engagement. This effort led to the development of the clinical candidate H3B-6545, a covalent antagonist that is potent against both  ERαWT/MUT, and maintains potency even in the context of ERα C530 mutations. H3B-6545 demonstrates significant activity and superiority over standard-of-care fulvestrant across a panel of ERαWT and ERαMUT palbociclib sensitive and resistant models. In summary, the compelling preclinical activity of H3B-6545 supports its further development for the potential treatment of endocrine therapy-resistant ERα+ breast cancer harboring wild-type or mutant ESR1, as demonstrated by the ongoing clinical trials (NCT03250676, NCT04568902, NCT04288089). SUMMARY: H3B-6545 is an ERα covalent antagonist that exhibits encouraging preclinical activity against CDK4/6i naïve and resistant ERαWT and ERαMUT tumors.


Asunto(s)
Neoplasias de la Mama , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Ensayos Clínicos como Asunto , Receptor alfa de Estrógeno/genética , Femenino , Fulvestrant/uso terapéutico , Humanos , Indazoles , Recurrencia Local de Neoplasia , Piridinas
4.
Integr Cancer Ther ; 11(1): 68-80, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21498474

RESUMEN

The present study aimed at evaluating the anticancer and radiosensitizing potential of juglone against a chemoresistant and radioresistant tumor (B16F1 melanoma) growing on C57BL/6J mice. Volume doubling time, growth delay, and median survival were used to assess the in vivo anticancer and radiosensitizing potential of juglone. In vitro radiosensitizing potential of juglone was studied using clonogenic, comet, and reactive oxygen species induction assays. Treatment of tumor-bearing mice with sublethal doses of juglone caused a dose-dependent inhibition of tumor growth as evident from the growth delay and median survival values. Comet assay using tumor tissue and blood showed differential toxicity of juglone, where higher levels of DNA damage was seen in tumor tissue compared with blood cells. Pretreatment of tumor-bearing mice with optimum dose of juglone before radiation resulted in significant tumor growth inhibition compared with radiation alone. From the clonogenic assay, the authors observed a sensitization enhancement ratio of 1.37 for the combination treatment compared with radiation alone. Furthermore, comet assay studies revealed the potential of juglone to enhance the radiation-induced DNA damage and cause a delay in its repair. Juglone pretreatment before radiation also resulted in a significant elevation in the intracellular reactive oxygen species levels compared with radiation alone. In conclusion, the results of this study show the potential of juglone to inhibit the growth of melanoma in vivo. The study also revealed the potential of juglone to augment the radiation-induced cell death of melanoma cells, which may be attributed to oxidative stress-mediated DNA damage and its delayed repair.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Naftoquinonas/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Femenino , Masculino , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/metabolismo , Melanoma Experimental/radioterapia , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo
5.
Photochem Photobiol ; 86(6): 1364-72, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20735808

RESUMEN

We report the design and development of an optical fiber probe-based Helium-Neon (He-Ne) low-level laser therapy system for tissue regeneration. Full thickness excision wounds on Swiss albino mice of diameter 15 mm were exposed to various laser doses of 1, 2, 3, 4, 6, 8 and 10 J cm(-2) of the system with appropriate controls, and 2 J cm(-2) showing optimum healing was selected. The treatment schedule for applying the selected laser dose was also standardized by irradiating the wounds at different postwounding times (0, 24 and 48 h). The tissue regeneration potential was evaluated by monitoring the progression of wound contraction and mean wound healing time along with the hydroxyproline and glucosamine estimation on wound ground tissues. The wounds exposed to 2 J cm(-2) immediately after wounding showed considerable contraction on days 5, 9, 12, 14, 16 and 19 of postirradiation compared with the controls and other treatment schedules, showing significant (P < 0.001) decrease in the healing time. A significant increase in hydroxyproline and glucosamine levels was observed for the 2 J cm(-2) irradiation group compared with the controls and other treatment groups. In conclusion, the wounds treated with 2 J cm(-2) immediately after the wounding show better healing compared with the controls.


Asunto(s)
Láseres de Gas/uso terapéutico , Terapia por Luz de Baja Intensidad/métodos , Regeneración/efectos de la radiación , Animales , Relación Dosis-Respuesta en la Radiación , Femenino , Hidroxiprolina/metabolismo , Terapia por Luz de Baja Intensidad/instrumentación , Masculino , Ratones , Fibras Ópticas , Regeneración/fisiología , Piel/lesiones , Piel/metabolismo , Piel/efectos de la radiación , Cicatrización de Heridas/fisiología , Cicatrización de Heridas/efectos de la radiación
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