3JC48-3 (methyl 4′-methyl-5-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)-[1,1′-biphenyl]-3-carboxylate): a novel MYC/MAX dimerization inhibitor reduces prostate cancer growth

Shukla, Sanjeev; Fletcher, Steven; Chauhan, Jay; Chalfant, Victor; Riveros, Carlos; Mackeyev, Yuri; Singh, Pankaj Kumar; Krishnan, Sunil; Osumi, Teruko; Balaji, K.C.

doi:10.1038/s41417-022-00455-4

Cited by 6 publications

(7 citation statements)

References 29 publications

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“…We used an alternate strategy to improve the efficacy of c-Myc inhibition. The basic helical structure and zipper protein of c-Myc forms an obligate heterodimer with its partner MYC-associated factor X (MAX) to function as a transcription factor [18]. The addition of a second-generation small molecular MYC/MAX heterodimerization inhibitor 3JC48-3 to MT-1 enhanced the efficacy of PC growth inhibition in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…As c-Myc is a prolific transcription factor involved in a variety of normal cellular functions, a perceived risk of c-Myc targeting is systemic toxicity. We have previously demonstrated that 3JC48-3 as a novel c-Myc/MAX dimerization inhibitor, is tolerable in animal models with no change in either weight or signs predictive of adverse outcomes [18]. We postulated that this favorable side effect profile may be in part due to residual and necessary c-Myc transcriptional activity because of the partial inhibition of c-Myc/Max dimerization and binding to DNA activation sites, as the concentration required for complete inhibition may be too high [28].…”

Section: Discussionmentioning

confidence: 99%

“…Because we have previously shown that c-Myc is a transcriptional repressor of PrKD [18], we expected c-Myc inhibition by MT-1 to increase PrKD expression and kinase activity resulting in increased downstream substrate phosphorylation. Following treatment of PC-3 cells with MT-1 at concentrations of 0.1 and 0.5 µM for 24 h (Figure 1E), the total cell lysates demonstrated a 0.87-fold decrease and 1.2-fold increase in c-Myc and PrKD protein levels, respectively (Figure 1E).…”

Section: Mt-1 Treatment Of Pc3 Cells Increased Prkd Protein Levels An...mentioning

confidence: 99%

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The Bivalent Bromodomain Inhibitor MT-1 Inhibits Prostate Cancer Growth

Shukla

Riveros

Al-Toubat

et al. 2023

Cancers

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Bromodomains (BD) are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation of several genes including protooncogene cellular myelocytomatosis (c-Myc). c-Myc is difficult to target directly by agents due to its disordered alpha helical protein structure and predominant nuclear localization. The epigenetic targeting of c-Myc by BD inhibitors is an attractive therapeutic strategy for prostate cancer (PC) associated with increased c-Myc upregulation with advancing disease. MT-1 is a bivalent BD inhibitor that is 100-fold more potent than the first-in-class BD inhibitor JQ1. MT-1 decreased cell viability and causes cell cycle arrest in G0/G1 phase in castration-sensitive and resistant PC cell lines in a dose-dependent fashion. The inhibition of c-Myc function by MT-1 was molecularly corroborated by the de-repression of Protein Kinase D1 (PrKD) and increased phosphorylation of PrKD substrate proteins: threonine 120, serine 11, and serine 216 amino acid residues in β-Catenin, snail, and cell division cycle 25c (CDC25c) proteins, respectively. The treatment of 3D cell cultures derived from three unique clinically annotated heavily pretreated patient-derived PC xenografts (PDX) mice models with increasing doses of MT-1 demonstrated the lowest IC50 in tumors with c-Myc amplification and clinically resistant to Docetaxel, Cabazitaxel, Abiraterone, and Enzalutamide. An intraperitoneal injection of either MT-1 or in combination with 3jc48-3, an inhibitor of obligate heterodimerization with MYC-associated protein X (MAX), in mice implanted with orthotopic PC PDX, decreased tumor growth. This is the first pre-clinical study demonstrating potential utility of MT-1 in the treatment of PC with c-Myc dysregulation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Mt-1 Treatment Of Pc3 Cells Increased Prkd Protein Levels An...mentioning

confidence: 99%

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The Bivalent Bromodomain Inhibitor MT-1 Inhibits Prostate Cancer Growth

Shukla

Riveros

Al-Toubat

et al. 2023

Cancers

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“…Some of the earliest MYC inhibitor studies identified two unrelated small molecules, 10058-F4 and 10074-G5, among others that bind distinct regions within the c-MYC bHLHLZ domain and stabilize the monomer, thus interfering with MYC-MAX heterodimerization and its association with DNA targets. − Lack of efficacy in established CDX models, mice bearing human androgen-independent prostate cancer cells or human Burkitt’s lymphoma cells, was attributed to unfavorable pharmacological profiles including rapid metabolism and low tumor penetration. , Although, some success was later reported using 10058-F4 in MYCN transgenic mice . An improved second generation analogue of 10074-G5, termed 3jc48-3, displaying greater potency in vitro and increased half-life, underwent preliminary testing in a high-grade prostate cancer PDX model. , Albeit a small sample size, 3jc48-3 was well-tolerated with evidence of slowing tumor growth reflecting the drug’s enhanced properties.…”

Section: In Vivo Evaluation Of Myc-max-dna Inhibitorsmentioning

confidence: 99%

Demystifying the Druggability of the MYC Family of Oncogenes

et al. 2023

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The MYC family of oncogenes (MYC, MYCN, and MYCL) encodes a basic helix−loop−helix leucine zipper (bHLHLZ) transcriptional regulator that is responsible for moving the cell through the restriction point. Through the HLHZIP domain, MYC heterodimerizes with the bHLHLZ protein MAX, which enables this MYC-MAX complex to bind to E-box regulatory DNA elements thereby controlling transcription of a large group of genes and their proteins. Translationally, MYC is one of the foremost oncogenic targets, and deregulation of expression of the MYC family gene/proteins occurs in over half of all human tumors and is recognized as a hallmark of cancer initiation and maintenance. Additionally, unexpected roles for this oncoprotein have been found in cancers that nominally have a non-MYC etiology. Although MYC is rarely mutated, its gain of function in cancer results from overexpression or from amplification. Moreover, MYC is a pleiotropic transcription factor possessing broad pathogenic prominence making it a coveted cancer target. A widely held notion within the biomedical research community is that the reliable modulation of MYC represents a tremendous therapeutic opportunity given its role in directly potentiating oncogenesis. However, the MYC-MAX heterodimer interaction contains a large surface area with a lack of well-defined binding sites creating the perception that targeting of MYC-MAX is forbidding. Here, we discuss the biochemistry behind MYC and MYC-MAX as it relates to cancer progression associated with these transcription factors. We also discuss the notion that MYC should no longer be regarded as undruggable, providing examples that a therapeutic window is achievable despite global MYC inhibition.

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“…However, these chemicals have limited clinical applicability due to their low potency, lack of selectivity, and poor pharmacokinetic behavior in vivo [ 21 , 22 ]. Despite significant efforts to optimize the two compounds, namely their derivatives JY-3-094 and 3jc48-3, resulting in varying degrees of improved potency, animal models have yet to demonstrate satisfactory tumor reduction performance [ [23] , [24] , [25] ]. Inhibiting c-Myc transcriptional activity can be also achieved by blocking the direct binding of c-Myc/Max to DNA using natural compounds like celastrol and celastrol-inspired triterpenoids [ 26 ], synthetic mimetics such as JKY-2-169 [ 27 ], or small molecule inhibitors including MYRA-A [ 28 ], NSC308848 [ 29 ], and KSI-3716 [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and activity evaluation of 2-iminobenzimidazoles as c-Myc inhibitors for treating multiple myeloma

Li,

Wang,

Yin

et al. 2024

Heliyon

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3JC48-3 (methyl 4′-methyl-5-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)-[1,1′-biphenyl]-3-carboxylate): a novel MYC/MAX dimerization inhibitor reduces prostate cancer growth

Cited by 6 publications

References 29 publications

The Bivalent Bromodomain Inhibitor MT-1 Inhibits Prostate Cancer Growth

The Bivalent Bromodomain Inhibitor MT-1 Inhibits Prostate Cancer Growth

Demystifying the Druggability of the MYC Family of Oncogenes

Design, synthesis, and activity evaluation of 2-iminobenzimidazoles as c-Myc inhibitors for treating multiple myeloma

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