Approach

The Genesis of dual-acting molecules with low toxicity for multiple tumors in pediatric and adults

Underlying Cancer Therapeutics

Eric Rubenstein, M.D. Oncologist

As a practicing oncologist and physician investigator over the years; I’ve been amazed by the advent of precision medicine including monoclonal antibodies, ADC’s, tyrosine kinase inhibitors, and more recently checkpoint inhibitors, bispecific antibodies, and cellular therapeutics. These compounds have yielded enormous gains, but the success story applies to only a subset of patients in the clinic.
Tragically, there are many cancers with high mortality and morbidity for which the standard of care has improved little over the past 2 decades and remains “substandard.” If I had one wish to make it would be to create a new universal cancer therapeutic that could serve as a ‘core’ agent to be used synergistically with precision therapeutics. Expanding on this, I’d like to see technology produce drugs that allow all patients live “better for longer” as an opposed to “longer for worse.” We need drugs that are more effective and less toxic, always prioritizing patient reported outcomes over nominal gains in progression free and overall survival.

Universal Applicability to Multiple Tumor Types for Pediatric and Adult Cancers

Dr. Peter Crooks

“The cancer conundrum is that cancer manifests as a number of different diseases, not just one.”

The fundamental question- what can be done to slow tumor growth as well as stop metastasis. Given the number of pathways involved, the complexity of the cancer millieu and the immense propensity for developing resistance, the search for a universal oncolytic continues to be a lofty goal. For all of these reasons, we chose to look at the primordial tubulin pathway as a starting point but in an entirely new way.

The Starting Point

Tubulin Inhibitors

We target the Colchicine Domain

Microtubules are critical in cellular division or mitosis, creating the scaffolding upon which a cell can replicate its DNA, creating a copy of chromosomes. Tubulin is a family of proteins that polymerize to form microtubules which are a central component of cellular architecture. Unlike other anticancer drugs (e.g. alkylating, kinase, etc.) antimitotics target mitosis which is only relevant during cell division. For rapidly proliferating cancer cells, this is a relevant target since it minimizes the impact to healthy cells.
For this reason, tubulin has been a target for pharmaceutical development since the 1960s. Recently, the colchicine domain has garnered new attention as a target-though toxicity issues have hampered broad pursuits by industry.
However, the colchicine binding site possesses advantages compared with other tubulin-targetting agents, by effecting the tumor microenvironment via the inhibition angiogenesis as well as overcoming P-glycoprotein mediated multidrug resistance. To minimize toxicity potential, we started with botanical based structures.

About Our Lead Molecule MLS-222QLD

Low Toxicity

Both in vivo tested and in proprietary in silico modeling that includes: hERG, Liver Tox, Mitochondrial Tox and Ocular Toxicity

High Efficacy

Designed with M-Life’s P2L and MiST platforms for receptor docking, as well as cell phenotypical performance and tested in animals and cell cultures.

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Optimized Synthesis

High efficiency, scaled and patent pending synthesis.

Cellular division wherein tubules can be readily seen (the filaments that form). They serve a critical role in division without which division is not possible.

The Finalist Molecules

Dual Inhibition of Tubulin & NFkB

For More Information About Our Process, Tubulin and NF-kB See the Links Below:

Augmenting tubulin-based activity, these molecules have a second active moiety targeting NF-κB. NF-κB’s inhibitory complex forms in the cytoplasm, is important for regulating programmed cell death (apoptosis). It functions as a pro-survival transcription factor by inducing the expression of antiapoptotic genes, such as the Bd-2 family members and caspase inhibitors, and antioxidant genes, such as MnSOD and FHC. NF-κB is implicated in the resistance of many cancer cells to chemotherapeutic drugs, radiation, and programmed cell death cytokines. Hence, inhibition of IKK-driven NF-κB activation offers a strategy for the treatment of different malignancies and can convert inflammation-induced tumor growth to tumor regression.

The combination NF-κB and colchicine-based tubulin inhibition provides a synergistic therapeutic effect, both decreasing cancer cell replication and foiling cancer cells ability to hijack the apoptosis pathway. Since both moieties are present in one molecule, the pharmacokinetics are consistent. Additionally, a singular molecule avoids compounding toxicities for two different drugs. Initial development efforts centered on efficacy–both docking and phenotypical (animal & human) assessments by M-Tubulin’s parent company M-Life. These are represented in the top two tiers of the adjacent graphic. Algorithm ensembles within the Pattern-to-Lead P2L™ and Molecular in Silico Tomography (MiST™) platforms included data across various cancer types as well as many cell lines, accomplished with data from a variety of sources. The objective, to identify the key molecular features, or active moieties most- frequently associated with efficacy while diminishing additive toxicities that often lead to drug failures.