Preclinical analysis of the efficacy of a LIM Kinase inhibitory compound for primary and metastatic cancer chemotherapy – LIMINIB

Tumor metastasis is the primary cause of death of cancer patients. Moreover, the emergence of drug resistant tumor cells substantially limits the clinical usefulness of drugs used in current chemotherapy. Development of new therapeutics effective against drug-resistant cancers and preventing tumor metastasis is urgently needed.

Among the mechanisms involved in metastatic evolution, it has been demonstrated that the level of cofilin activity, a protein that plays a central role in actin microfilaments dynamics, is directly related to invasion, extravasations and metastasis of tumors. Indeed, a growing amount of published results indicate that inhibitors targeting the cofilin pathway will have therapeutic benefit in combating metastasis Phosphorylation of the actin binding protein cofilin by LIM Kinase (LIMK)is the last step of a cascade that regulates actin dynamics. It has been shown that LIMK plays a central role in regulating microfilaments dynamics and cell motility.
LIMK is over expressed in invasive carcinomas and has been proven to be a relevant therapeutic target. So far, despite intensive researches, no LIMK inhibitors, showing activity in anti cancerous therapy has been described, however.

We have identified and patented (international patent) a LIMK inhibitor, cell permeable and wich is reversible.
This inhibitor, which we have named Liminib, blocks cell motility, by disorganizing actin microfilament networks. It also induces a stabilization of the microtubule network, with a mechanism of action different to that of taxanes. Indeed, it does not interact directly with tubulin, the building-block of microtubules, but on an associated protein. Liminib shows toxicity on several cancerous cell lines, including drug resistant cell lines.
This compound shows thus both anticancerous and antimetastatic properties.
Results from “pilot” preclinical studies are promising, showing a good therapeutic efficacy together with a good tolerance.
A study, which aims to determine Liminib pharmacokinetics and to study its toxicity is currently undergoing.

The aims of the present proposal are, at the preclinical level:
- To check, using validated animal models and larger studies, the efficacy of Liminib for cancer therapy;
- To test, at the preclinical level on validated animal models, the potential benefit of a Liminib treatment over existing chemotherapy (taxanes);
- To assay the efficacy of Liminib on a relevant animal model of metastatic tumor.
In parallel, efforts will be done to conceive and develop an optimized method for Liminib synthesis, to facilitate the scaling-up and to reduce the synthesis costs, in view of an industrial application. The synthesis of appropriate structural active analogues (pro-drugs) will also be developed with the aim to optimize its Liminib solubility.
Finally, experiments will be done to precise Liminib mechanism of action, in order to define acute surrogate markers of its therapeutic efficacy.

If successful results are obtained, this will greatly reduce the risks of the patent exploitation and boost its value. The principal way of technology transfer under consideration is licensing or partnership with a start-ups or pharmacological industry. People directly involved in this proposal do not discard the possibility to later on create their own start-up, if a solid business plan can be built.