전문가기고 [Laura Soucek] Trends in the development of a clinically-viable Myc inhibitor


Trends in the development of a clinically-viable Myc inhibitor

Vall d’Hebron Institute of Oncology, Jonathan R. Whitfield1 and Laura Soucek)

Myc and cancer

Myc is currently one of the “most wanted” targets in cancer therapy (1). The Myc family consists of three functionally related genes: c-myc (MYC), l-myc (MYCL), and n-myc (MYCN) (2). MYC was the first gene to be discovered in this family, almost four decades ago, due to homology with the viral gene v-myc, carried by the Avian virus Myelocytomatosis, which gave the name to the whole family. The other two members of the family, MYCL and MYCN were found expressed in lung cancer and brain development, respectively. All three proteins (from now on, Myc) fall in the category of intrinsically disordered proteins (IDPs), not having a well-defined three-dimensional structure in solution (1). However, Myc displays a basic-loop-helix-leucine zipper (bHLHLZ) domain at its C-terminus that allows it to dimerize with a similar protein called Myc-associated protein X (MAX), assuming a conformation suitable to DNA binding at transcriptional binding sites called E-boxes (Enhancer-boxes) (3). Together with MAX, Myc functions as a nuclear transcription factor that coordinates several intracellular and extracellular programs that contribute to the development and maintenance of tumors. In physiological conditions, it is finely tuned to be expressed only transiently, to allow cells to efficiently progress through the cell cycle (mainly, but not limited to, contributing to the G1-S transition). However, in cancer, Myc regulation is lost, due to increased Myc copy number, or alterations in Myc transcription, translation or even protein stability. In general, compared to other infamous oncogenes, Myc is not frequently found mutated in cancer, but it is instead induced and acts as an essential conduit downstream of other oncogenic signals, which all funnel through Myc in the nuclei of the cells to execute the transcriptional programs that ultimately lead to uncontrolled tumor growth (4). In this context, deregulated, tonic signaling through Myc can be as tumorigenic as elevated levels of it (5).

Myc has been shown to contribute to essentially all hallmarks of cancer: it promotes cell division, it contributes to angiogenesis and cross-talk with the tumor microenvironment (6), it is responsible for blocking the anti-tumor immune response (7) and it even confers better survival chances and resistance to many standard of care therapies (8).

Because of all these reasons, Myc is considered a particularly appealing target for cancer treatment. Nevertheless, no Myc inhibitor is available in the clinic yet and the race is on to develop one (9).

Myc as an “undruggable” target

Myc has long been considered a challenging – if not impossible – therapeutic target, mainly because of technical reasons, but also due to the preconceived notion that inhibiting it would cause severe potential side effects in normal proliferative tissues. From the technical point of view, the difficulties are associated to the intrinsically disordered nature of the protein, challenging to tackle with standard molecule approaches, lack of an enzymatic pocket and its nuclear localization (10).

However, different approaches have been used to circumvent these issues. Here, we are mentioning some of the best characterized strategies to date (for a complete review, refer to (9)).

1.Interference with Myc transcription

Direct strategy:

G-quadruplexes are 4-stranded DNA structures formed in guanine-rich regions. They can act as silencer elements, repressing transcription of proximal genes. The MYC promoter happens to have such a structure (11). Several studies have shown that some small molecule ligands (e.g. cationic porphyrins, quindolines) can stabilise G-quadruplexes in the MYC promoter, like CX-33543 or quarfloxin, resulting in MYC downregulation (12,13) (Figure 1). The Phase III trials for quarfloxin are currently not proceeding due to high albumin binding, but other G-quadruplexes are in the pipeline for further development (14).

Direct strategy:

Figure 1. Schematic of mechanism of action of a G-quadruplex stabilizer (created with Biorender).

Indirect strategy: BET bromodomain inhibitors.

The BET bromodomain and extra-terminal domain inhibitors (BETi) have been found to be able to displace the bromodomain chromatin regulators from the large super-enhancers of genes (Figure 2). The first one to demonstrate this action against MYC as well was JQ1 in multiple myeloma, followed by Burkitt’s lymphoma and acute myeloid leukemia, where the Myc gene is amplified (15-17). It is now clear that JQ1—and other BET inhibitors— are not specific for MYC, but act on multiple genes within cancer cells that might contribute to the tumorigenic phenotype (18-20). Because of that, despite their often poor selectivity, several BET inhibitors are currently in early phase clinical trials in various malignancies (for a review, see (21).

Figure 2. Schematic of mechanism of action of a BETi such as JQ1 (created with Biorender).

2.Interference with Myc translation

Antisense Oligonucleotides (ASOs):

One of the first strategies tested against Myc has been the use of ASOs in order to induce degradation of Myc mRNA (22,23) (Figure 3). This approach has demonstrated some success in multiple cell lines and was tested in the clinic already two decades ago, where it got as far as Phase II clinical trials (24). Not much is reported regarding why it has not been pursued further than that.

Figure 3. Mechanism of action of ASOs (created with Biorender).

siRNA or shRNA

A similar approach is based on siRNA or shRNA, which takes advantage of Dicer and RISC complex to target Myc RNA before it can be translated into a functional protein (Figure 4). Once again, this approach recently reached clinical trials, where it was tested as Myc RNAi (DCR-MYC) encapsulated in lipid nanoparticles (25). Unfortunately, the trial did not meet expectations of Myc knock-down or efficacy and was discontinued.

Figure 4. Mechanism of action of shRNA and siRNA (created with Biorender).

It should be noted that, in both types of approach, a different siRNA (or shRNA) is needed for each member of the Myc family and it requires the encapsulation in nanoparticles for its delivery in vivo.

Interference with IRES-dependent translation

Myc mRNA can be translated both by 5’ cap- and internal ribosome entry site (IRES)- dependent mechanisms (26), offering the opportunity to regulate Myc translation by targeting this process (Figure 5).
One possibility is to inhibit mTOR itself or upstream controllers of its activity (PI3K/PTEN/AKT and Ras/Raf/MEK/ERK). In this context, a small molecule inhibitor of eIF4A, silvestrol, appeared effective in reducing Myc translation and inhibiting tumor growth (27). Multiple mTOR and mTORC1/2 kinase inhibitors are currently approved for clinical use (9), but their impact is clearly not limited to Myc alone.
Another small molecule inhibitor called saracatinib was also found to inhibit the ERK1/2-MNK1-eIF4E-mediated cap-dependent translation of Myc (28).

Figure 5. Schematic of 5’CAP-dependent Myc mRNA translation and its inhibition (created with Biorender).

3. Inhibitors of Myc dimerization and DNA binding

Small molecules

After antisense, other early attempts to inhibit Myc aimed at interfering with Myc/MAX interaction and/or preventing their binding to DNA. The first attempts were through small molecules (29,30). Most small molecules, unfortunately, have been described – at least until recently – as frequently suffering from poor bioavailability (30,31). However, more recently, small molecule inhibitors have been developed by various novel techniques and are finally starting to show better in vivo capabilities. To mention some molecules directed to disruption of Myc/MAX dimers (Figure 6a):
Small molecule 3jc48-3 is related to one of the earliest described compounds (10074-G5) and displayed more potent activity as well as a 17 hour intra-cellular half-life (32), although no further in vivo studies have been reported. Mycro3, on the other hand, was effective in vivo when administered by oral gavage, increasing survival in mouse models of pancreatic cancer (33). In addition, KJ-Pyr-9 is an inhibitor found in a Kröhnke pyridine library; it has a very low KD (6.5 nM) and blocks the growth of Myc-amplified human cancer cell line xenografts and can so penetrate the blood-brain barrier (34). Novel computational techniques are also being used to virtually screen binding to different intrinsically disordered protein conformations, and compounds were identified with micromolar affinity for MYC (35).
Among other compounds that can disrupt binding to DNA, we would like to mention KSI-3716, which was effective in mouse models of bladder cancer (36,37) (Figure 6b).

Figure 6. Schematic of the mechanism of action of a) a putative Myc/MAX dimer destabilizer; b) a potential inhibitor of Myc/MAX binding to DNA (created with Biorender).

Disappointingly, further development of these promising molecules has not been reported. Given the number of effective small molecules out there that are hampered by in vivo delivery issues, it would also be interesting to see more attempts at incorporating these compounds into nanoparticles. To this end, MI1-PD is an integrin-targeted lipid-encapsulated nanoparticle formulation of a Myc-MAX dimerization inhibitor that showed in vivo efficacy in a mouse model of multiple myeloma (38).
A contrasting approach would be to stabilize Myc’s binding partner MAX, thus occupying DNA target sites with MAX homodimers and preventing MYC transcriptional activity (39). Recently such compounds have been described as antagonizing MYC-dependent gene expression in cells and delaying growth of MYC-driven tumors (40) (Figure 7).

Figure 7. Schematic of the mechanism of action of a MAX/MAX dimer stabilizer (created with Biorender).

Mini-proteins or protein domains

Several peptides and mini-proteins based on domains from Myc family members have been described as potential therapeutics tools. The first and most characterized is Omomyc, a mutant MYC bHLHLZ domain, functioning as a very efficient Myc dominant negative (41,42). Omomyc functions through several mechanisms of action, forming heterodimers with Myc unable to bind DNA, but also homodimers and heterodimers with MAX, which occupy E-boxes with transcriptional inactive complexes (Figure 8). Omomyc was initially used as a transgene in multiple mouse models of cancer to establish the proof-of-concept that Myc inhibition is feasible, effective and lacks significant side effects (43-49). Recently, the recombinantly-produced Omomyc mini-protein has been shown to have unexpected cell penetrating properties and therapeutic activity in NSCLC (non-small-cell lung cancer), both in vitro and in vivo, and it is being developed as a drug, expected to reach clinical trials in 2021 (10,50).
It should be noted that, based on the Omomyc basic region, some smaller peptides have been developed for interference with MYC/MAX binding to the E-box. Such peptides recapitulated at least one of Omomyc’s mechanisms of action and have shown promise in vitro, but remain to be tested in vivo (51).
Another mini-protein modulating the Myc network has been derived from MXD1: Mad. Like Omomyc, Mad dimerizes with MAX and binds the E-box, interfering with Myc-mediated transcription in cell models (52).

Figure 8. Omomyc mechanism of action as Myc dominant-negative (created with Biorender).

4.Induction of Myc degradation

In physiological conditions Myc has a short half-life (approximately 20 minutes), mainly determined by its phosphorylation and consequent ubiquitination. Hence, a potential strategy for its inhibition is to increase the activity of ubiquitinases or inhibit deubiquitinases (Figure 9).

To mention some examples of these applied strategies:
Oridonin has been associated to activation of FBW7-mediated degradation of MYC (53). Its derivatives reached clinical trials (e.g., HAO472 for leukemia treatment), however its anti-cancer function has not been linked to MYC only.

For what specifically concerns MYCN, it has been shown that complexes with Aurora-A kinase can protect it from proteasomal degradation (54), hence Aurora-A inhibitors (i.e. MLN8054 and MLN8237) have been developed to overcome this protection. Unfortunately, MLN8054 was terminated by Millenium in 2008 due to side effects (55), but the second generation inhibitor MLN8237 (Alisertib) is currently being evaluated in multiple Phase II and III studies and some positive results have been reported (56-58).

Small molecule inhibitors against another ubiquitin ligase, HUWE1, have also been shown to induce Myc and Miz1 degradation (59).

Figure 9. Schematic of induction of Myc degradation by modulation of the ubiquitin pathway (created with Biorender).

Alternatively, the tumor suppressor protein phosphatase 2A (PP2A) destabilizes MYC by targeting serine 62 of MYC (60). Cellular inhibitors of PP2A (the SET oncoprotein and CIP2A, the cancerous inhibitor of PP2A) are increased in human cancers and lead to overexpression of MYC (61). Thus, inhibitors of SET and CIP2A can reduce MYC activity (62,63) and are in preclinical development, though they would also act on other targets besides MYC alone.

A potential arrival to this field could be PROTACS – proteolysis targeting chimeras – that couple a protein-targeting ligand with an E3 ubiquitin ligase (64). This approach relies on degradation of the target upon binding. Whether this promising new approach will be applicable to a protein like Myc with such a short half-life remains to be seen, but indirect targeting with a pan-BETi PROTACS ARV-771 reduced MYC expression and caused xenograft tumor regression in prostate cancer mouse models (65). Clinical trials have not been announced as yet.

5. Synthetic lethality

In addition to the plethora of strategies already described, other indirect approaches have also been employed to get around the issues involved with direct Myc targeting. These include synthetic lethal approaches that could in theory target any specific dependency of Myc-driven tumor cells. Many diverse targets have already been identified, including SAE1/2 (66), CDK2 (67), CDK9 (68), PIM kinase (69), and many more involved in metabolism (for a more complete discussion see (9)).

Challenges and opportunities

We can all agree that this is an exciting time in the Myc inhibition world: many groups – and now also Biotechs and Big Pharma – are involved in the hunt for the first and best Myc inhibitor that can find its application in cancer patients. With so many strategies now to tackle this previously undrugged and seemingly undruggable target, it finally feels like clinical success is fast approaching. We all feel hopeful that such a historical milestone will revolutionize cancer treatment and potentially become applicable to multiple types of indications in oncology.


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