Living cells depend on a critical balance between positive and negative regulation of signaling systems. These systems allow cells to adapt to environmental changes, whether introduced from the environment by diet, exposure to drugs or radiation, or defects in metabolism including diabetes and inborn enzyme deficiencies such as Gaucher, von Hippel-Lindau, and neurofibromatosis type 2 disease. The normal functioning of healthy cells is a marvel of multiple continual small adjustments in systems regulating growth and metabolism. These "balancing" mechanisms are mediated through a series of off/on switches, which keep cells from responding too much or too little to the constantly changing environment.

Lixte designs compounds to attack key signaling pathways altered in cancer and other serious diseases. Important switch mechanisms altered in many serious diseases are the rapid and reversible modification of signaling enzymes through the addition or removal of small chemical groups (phosphate and acetyl moieties). Lixte's proprietary compounds target specific components of these switch mechanisms: the LB-100 series inhibit removal of phosphate groups (phosphatase inhibitors) and the LB-200 series inhibit removal of acetyl groups (deacetylase inhibitors). Because the selected targets are multifunctional enzymes, this approach has resulted in the discovery of novel agents with potential value in the treatment of seemingly disparate diseases.

In animal models of cancer and cellular models of inborn metabolic diseases, modulation of regulatory pathways by Lixte compounds has demonstrated potential therapeutic benefit. Lixte has awarded and pending patents for the compounds and the potential uses shown in the Pipeline Chart.



Regulation of cell division in cancers is abnormal because of acquired (as opposed to inborn) gene abnormalities (mutations). This faulty regulation often provides the cancer cell a growth advantage over the normal cell, allowing the cancer to spread locally and/or distantly (metastasis). This growth advantage comes at a cost to the cancer cell, however, because it is accompanied by a loss of function of back-up systems needed for survival under stress including exposure to anti-cancer drugs or radiation. On the other hand, normal cells possess a full complement of regulatory systems and are often not as vulnerable to growth inhibition or killing even though an important regulatory pathway is transiently altered by a drug. Lixte exploits this differential sensitivity to cell killing between the cancer cell and normal cell to enhance the effectiveness of cancer treatment.

Lixte has targeted an enzyme, protein phosphatase 2A (PP2A), which removes phosphate groups from proteins involved in control of cell growth and repair of DNA damage caused by chemotherapy and/or radiation. When PP2A is inhibited during chemotherapy or radiation treatment, the PP2A-mediated defense mechanisms, which ordinarily are activated to protect cells from fatal DNA damage fail to function, enhancing the cancer killing effects of the treatment without enhancing toxicity to normal cells which can compensate for PP2A inhibition. Because of the universality of this mechanism, toxicity permitting, the lead compound, LB-100 has the potential for improving the effectiveness of current and evolving chemo- and radiotherapy regimens for many, if not all, cancers.

Despite the importance of PP2A to the survival of cancer cells during aggressive chemotherapy/radiotherapy regimens (an important cause of drug resistance), no inhibitors of PP2A are currently approved for clinical use. Targeting PP2A has not been clinically exploited presumably because of concern that inhibition of a protein with multiple functions would be associated with unreasonable toxicity. Lixte's large animal studies, however, suggest that the first of its PP2A inhibitors, LB-100, can be given intermittently at significant (enzyme-inhibiting doses) with no observable toxicity and daily for 5 days without encountering limiting toxicity. Two decades ago, a naturally occurring inhibitor of PP2A, the antibiotic fostriecin, was evaluated in Phase I studies sponsored by the National Cancer Institute because of its broad spectrum of anti-cancer activity in model systems. Fostriecin was given intravenously daily for 5 days without encountering dose-limiting toxicity. However, the trials were discontinued before the maximum tolerable dose could be determined because of inadequate drug supply of this natural product. The reported toxicity profile of fostriecin in large animal studies and in those patients showing toxicity in the aborted clinical trials is similar to that found in animal studies of Lixte's lead PP2A inhibitor, LB-100.

LB-100 has been approved by the Food and Drug Administration for Phase I study in patients with advanced cancers given alone and then in combination with a widely used anticancer drug, docetaxel. (In animal studies, LB-100 shows dose-dependent enhancement of docetaxel activity against human breast cancer xenografts). On January 4, 2017, the Lixte issued a news release to announce the publication online of Phase 1 results of the Company’s novel anti-cancer compound in Clinical Cancer Research, entitled “Safety, tolerability, and preliminary activity of LB-100, an inhibitor of protein phosphatase 2A, in patients with relapsed solid tumors.” Ten (46.7%) of twenty-one patients receiving at least 2 cycles of LB-100, a small molecule inhibitor of protein phosphatase (PP2A), achieved stable disease without limiting toxicity for up to 15 cycles of therapy, including one patient with pancreatic cancer who had a partial regression. PP2A has long been recognized as a potentially important cancer treatment target, but its inhibition was thought to be too toxic for clinical use.

This Phase 1 clinical trial demonstrated the safety and tolerability of PP2A inhibition in patients with refractory solid tumors. In numerous animal models of cancer, inhibition of PP2A by LB-100 enhanced the anti-tumor activity of standard chemotherapy drugs and radiation without significantly enhancing their toxicity by altering cell cycle regulation and the DNA-damage repair response pathways. The mechanism by which LB-100 used alone apparently inhibited the growth of a variety of cancers in patients in the recently completed Phase 1 clinical trial is not clear, but PP2A activity is reduced by mutation directly or indirectly in many cancer types, rendering them vulnerable to pharmacologic inhibition of PP2A. The Company believes that the results reported in Clinical Cancer Research support further development of LB-100 alone and in combination with standard cytotoxic regimens for a broad spectrum of tumors.

The Company presented a late-breaking abstract entitled “Protein phosphatase 2A inhibition with a novel small molecule inhibitor, LB-100 achieves durable immune-mediated anti-tumor activity when combined with PD-1 blockade in a pre-clinical model” as a poster (abstract number LB-193) at the American Association for Cancer Research (“AACR”) Annual Meeting 2017 in Washington, D.C. on April 4, 2017. This research was done in collaboration with scientists at the National Institute of Neurological Disorders and Stroke at the National Institutes of Health.

The research showed that, in an animal model, the Company’s lead clinical compound, LB-100, has synergistic potential, in conjunction with immune checkpoint blockade, to support the investigation of its ability to enhance immunotherapy in the clinic. LB-100 is a novel, first-in-class, small molecule inhibitor of protein phosphatase 2A (PP2A) that recently completed a Phase 1 clinical trial in patients with advanced cancer.

Based on a number of published pre-clinical studies, the Company had expected that LB-100 would be therapeutically most useful when combined with cytotoxic anti-cancer drugs and x-ray. However, the new pre-clinical immunotherapy data presented at AACR raises the possibility that LB-100 also enhances the efficacy of so-called 'immune checkpoint blockers'—agents that allow the patients' own immune system to attack their own cancers. If LB-100 potentiates the effectiveness of immunotherapy in the clinic, the scope of its potential applications in cancer treatment would be significantly increased.


PP2A mediates a number of different signaling pathways and is of fundamental importance to several otherwise seemingly unrelated disease entities. For example, PP2A is an essential component of the response of normal cells to deprivation of oxygen (ischemia). During ischemia, there are abnormal increases in the amounts of PP2A in tissues, particularly in blood vessels, which appear to contribute to the extent of tissue damage. In animal models, inhibition of PP2A even instituted after the induction of acute ischemia reduces the extent of infarction. With additional funding, Lixte will seek to document the ability of LB-100 to decrease tissue damage in models of stroke, myocardial infarction, and septic shock as has been reported for fostriecin and other inhibitors of PP2A.


Deacetylase inhibitors (DACi) are compounds which prevent the removal of a chemical group (acetyl group) modifier from many proteins. DACi have been studied primarily as modifiers of gene expression. When a class of proteins, the histones, is acetylated (carry an acetyl group) the genetic material (DNA) is more accessible (active) than when the acetyl groups are removed by deacetylases. Because disordered gene regulation is one hallmark of cancer cells, histone deacetylase inhibitors (HDACi) have been studied intensely as anti-cancer drugs and several have been approved for treatment of a relatively rare lymphoma of the skin. Lixte has developed a novel group of DACi which appear to be more stable and potentially possess broader actions than other HDACi and seeks to develop these compounds for potential treatment of specific non-malignant diseases as described below.


Two Lixte DACi, LB-201 and LB-205, inhibit the accelerated breakdown of "misfolded” proteins responsible for enzyme deficiencies in several hereditary diseases including Gaucher disease, neurofibromatosis 2 and von Hippel-Lindau disease. Exposure of cells with mutant proteins responsible for these diseases leads to stabilization of the proteins and potentially clinically significant increases in enzyme function. It appears that DACi inhibit the machinery responsible for the rapid destruction of these functional but mutant enzymes. Given the relatively low toxicity of HDACi in general, and of Lixte's compounds in particular, the LB-200 series of drugs have potential for the therapy of several inherited diseases for which better treatments are sorely needed. In particular, if LB-201 or LB-205 stabilizes the mutant protein causing Gaucher disease, glucocerebrosidase, in vivo as it does in vitro, the compounds may reduce the amount of enzyme replacement therapy required for treatment of non-neurologic Gaucher disease, currently costing in excess of $300,000 annually. Because LB-201 penetrates the blood brain barrier, it may be particularly beneficial in the treatment of neurologic forms of Gaucher disease in which enzyme replacement is currently ineffective.


Lixte's DACis have also been studied for the prevention and treatment of a variety of chronic and acute neurologic diseases. Because of the relatively low toxicity of HDACIs in general, Lixte's LB-201 was evaluated for its ability to reduce toxicity of various biochemical stresses in models of brain cell (neuron) injury. LB-201 was significantly protective against acute injury in these cell culture models, and a homolog, LB-205, reduced the extent of brain injury in rodent models of traumatic brain injury (TBI). Lixte hopes to engage a governmental or academic research group to assess the potential of its deacetylase inhibitors of brain injury, particularly for treatment of TBI.


Because acetylation/deacetylation signaling pathways are essential components of the regulated growth of many types of organisms, Lixte's compounds were assessed for anti-fungal activity. Several compounds of the LB-200 series are active against a panel of clinical isolates of fungal pathogens. A topical formulation of LB-201 is curative for two of the most common dermal fungal infections of humans and animals in a guinea pig model, which is generally accepted as a reliable surrogate for human skin infections. As there appears to be no toxicity associated with the topical use of LB-201, Lixte seeks a partner to proceed promptly to clinical development for this use.


Lixte is developing two additional novel classes of compounds, the LB-300 and LB-400 series. Molecules in these classes are designed to inhibit signaling pathways which Lixte believes will result in anti-cancer activity. In the LB-300 series, the targets are components of an enzyme complex important to cell division. In the LB-400 series, the target is an enzyme shown to be important in cell replication and in the pathogenesis of several types of cancers and certain non-malignant diseases. Prototypes of each series have anti-cancer activity against different types of human cancers in vitro and are presently being evaluated in animal models.

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