Conquest MYC: The light of day

The family of transcription factors consists of c-MYC, L-MYC and N-MYC and are the main regulators
of cellular processes such as cell proliferation, cell differentiation, cell cycle, and metabolism.
However, when these proteins are overactive, they accelerate these processes, leading to tumorigenesis
.
Therefore, MYC is one of the
most common dysregulated proteins in cancer.
However, MYC has long been considered "difficult to be drugged"
.

Because structurally it does not have a well-defined binding pocket, and it acts through protein-protein interactions, it provides less opportunity
for active drugs.
In addition, MYC also plays a role in the nucleus, regulating a series of signaling pathways and blocking can cause many toxicity problems
.

However, through unremitting efforts, some cell penetrating peptides or small molecule inhibitors or degradants targeting MYC have been developed and entered the clinical stage
.
At the EORTC-NCI-AACR conference in Barcelona, a cell-penetrating peptide called OMO-103 proved safe and potentially effective
in preliminary trials in humans.
In a small phase I trial of severely pretreated solid cancer patients, treatment was well tolerated and 8 participants were in stable
condition.
In addition, more drugs targeting MYC are also emerging, and the journey to conquer MYC is beginning to appear
.

The development of OMO-103 stemmed from the elucidating of the structure of MYC and its main protein partner, MAX, both of which contain closely related dimeric domains
.
But, oddly enough, MYC can only bind MAX, but MAX can bind to many other proteins, including itself
.
After comparing the structures of MYC and MAX, the researchers identified four charged amino acids
that could prevent MYC homodimerization.
When these repulsive amino acids are replaced with neutral amino acids, the resulting engineered peptide Omomyc can bind endogenous MYC
.

MYC–MAX dimers typically bind to DNA to regulate protein expression, while Omomyc binds to MYC to isolate natural transcription factors from their bound DNA
.
Omomyc–Omomyc and Omomyc-MAX dimers bind DNA simultaneously without altering transcription, blocking the function of
true MYC–MAX dimers.
Experiments with the Omomyc transgene showed that MYC inhibition was safe and could eradicate lung cancer
in mice.

Peptomyc launched the first phase of trials of OMO-103, a new version of Omomyc
, in April 2021.
The trial, which enrolled 22 patients with severely pretreated solid tumors, is further evidence that MYC suppression is safe and potentially effective
as an anti-cancer strategy.
The most common treatment-induced adverse events were infusion-related reactions, back pain, anaemia, and fatigue
.
In terms of efficacy, OMO-103 did not show a full or partial response, but 8 patients were stable, and 2 of them with pancreatic cancer received OMO-103 as a fourth-line treatment
.
Currently, Peptomyc is developing plans for its next clinical trial, prioritizing OMO-103 in combination with chemotherapy for pancreatic cancer
.

Currently, in addition to OMO-103, several other MYC-targeted molecules are emerging and may provide better pharmacological properties
.
For example, researchers at the University of Chicago just reported in the journal Nature Biotechnology that short peptides that mimic the MAX dimer domain could be used to inhibit MYC
in cells.

For example, a small molecule inhibitor called MYCi975 can destroy MYC–MAX dimers, promote MYC degradation and kill cancer cells
.
Phase I trials of the drug could take place
by 2024.

In addition, PROTAC-targeted degradants that bind and destroy MYC are also on the horizon
.
Kintor Pharmaceuticals will present preclinical results
of its dual c-MYC and GSPT1 gel degraders at an upcoming American Hematology Society meeting.
A team at the University of California, Berkeley, has just demonstrated in BioRxiv how the E3 ligase UBR5 degrades MYC and other transcription factors, providing a possible alternative pathway
for MYC-targeted degraders.

Omega Therapeutics is developing an mRNA-based approach to inhibit the expression
of MYC by modifying the genome structure.
The company began phase I trials
of its MYC-targeted drug OTX-2002 in October this year.

Monte Rosa Therapeutics' GSPT1 degrader MRT-2359 was also presented at the EORTC-NCI-AACR conference, Monte Rosa began research on MYC-targeted degradation drugs early on, and by screening its degradants in MYC turn-on and off-cell lines, they identified compounds
that control MYC activity.
GSPT1 degradants were subsequently screened in more than 500 cancer cell lines and 80 disease xenograft models, demonstrating their anti-cancer potential
.
A Phase I trial of MRT-2359 is currently underway
in MYC-driven tumors.
In addition, BMS is testing a GSPT1 degrader
called CC-90009 in a Phase I/II trial in acute myeloid leukemia.

References:

1.
Climbing cancer's MYC mountain.
Nat Rev Drug Discov.
 2022 Nov 11.

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