Other Inhibitor Drugs

Biologists call Signal Transduction Inhibitors any compound that blocks chemical signals from cell to cell. Most of the signal transduction inhibitors made into drugs effective in clinical use are kinase inhibitors. Other methods provoke the ongoing interest of scientists:

Proteasome inhibitors

Proteasomes are physiological micostructures that are part of the body’s waste management system.  They break down old and unneeded proteins that the cells need to be rid of. Compounds that stop or slow the action of the proteasomes are called proteosome inhibitors and scientists are looking at them as ways to fight cancer.  Some work so well they have gone through the drug development process and are approved for use against multple myelona. myeloma, mantle-cell lymphoma (MCL) and amyloidosis

Proteosome inhibitors have names that end in “zomib”

Ixazomib
Carfilzomib
Bortezomib

See also: Overview of Proteasome Inhibitor-Based Anti-cancer Therapies

PI3K/AKT/mTOR pathway

Biochemists have elucidated the PI3K/AKT/mTOR pathway in humans. It is a complex series of chemical reactions that serve to trigger cells to move – or not move – through the reproductive cycle. The series of reactions functions as a signal channel – it is referred to as signal transduction. The pathway has attracted the attention of medicinal chemists looking for ways to stop or slow cancer. Several inhibitor compounds have been found that interrupt parts of the pathway. These don’t always stop the cancer, partly because the overall pathway is so complex and cancers can find their way around blocked paths. And interfering with pathways can have unintended consequences. So even though the targeted medicines that come out of this research have fewer and less severe bodily side effects than old-style conventional drugs, they are not a free ticket to arresting cancer.

Scientists have developed mTOR inhibitors, AKT (protein kinase B) inhibitors, and P13K inhibitors. No AKT inhibitors have made it through development for use in clinical practice against cancer. mTOR inhibitors have hit the market, as have a few P13K inhibitors.

PI3K Inhibitors

PI3K is a class of enzymes that are classified as lipid kinases.  All kinases promote phosphorylation of chemicals in the cell, but lipid kinases specifically promote phosphorylation of lipids.  Cell membranes are rich in lipids. The PIK3 enzymes are important signal transducers and work (among elsewhere) in transmission of signals across the cell membrane.  There are many enzymes that could be considered PIK3 ones, and biologists have further divided them into threes classes: PI3K I, PI3K II, and PI3K III).

Scientists have found small molecule drugs that can stop the action of the enzymes. These are called Phosphatidylinositol 3-kinase inhibitor or phosphoinositide 3-kinase inhibitors but almost always designated by the abbreviation PI3K inhibitors.

Only three PI3K inhibitors have been approved by the FDA for treatment of cancer, and all of these came on the market only in the past few years. Idelalisib, Copanlisib and Duvelisib were all approved for lymphoma. Once enough patients have undergone treatment, doctors may be able to form a general opinion of this drug class. The PI3K inhibitors are often given in combination with other chemotherapy agents.

Research continues in this field – clinical trials of PI3K inhibitors are going on right now. Because the PI3K pathway gets messed up in an estimated one out of three cancers in humans there is hope this class of drugs will eventually prove effective in treatment of other types of cancer besides lymphoma.

Mitotic Inhibitors

These drugs stop cell division by tearing down the microtubule structures that form inside the nucleus when the chromosomes prepare to separate.
Mitotic inhbitors used in cancer treatment include the vinca alkaloids (vincristine, vinblastine, vinorelbine, and vindesine), taxanes (paclitaxel, docetaxel, and cabazitaxel), teniposide, etoposide, ixabepilone, estramustine, and eribulin.

IDH Inhibitors

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are mitochondrial enzymes and when there is a mutation the body overproduces D-2-hydroxyglutarate, which can drive growth of cancer. Drugs that inhibit these enzymes can be useful in cancer treatment.

In 2017 the FDA approved Enasidenib for acute myelogenous leukemia (AML). Ivosidenib inhibits the enzyme IDH-1, and the FDA approved it for leukemia treatment in 2018.  More on IDH inhibitors.

Notch inhibitors

It is known that some genes cause or contribute to the initiation and/or growth of cancer, and one are of research is whether blocking the action of those genes can stop or prevent the cancer. The Notch gene was first found in 1917 and now it turns out that the gene is implicated in a signaling system that is part of tumor growth.

Cell membrane surfaces have receptors now referred to as Notch receptors. In scientific literature there are referred to as Notch1 (or more formally Notch homolog 1 translocation-associated receptor), Notch2, Notch3, and Notch4.

A bunch of potential notch inhibitors are being investigated for their effects on cancer proliferation. There is an interest in combining them with hedgehog inhibitors. Cancer stem cells – aka tumor-initiating cells – are an area in which scientists think notch inhibitors might be helpful. However, Nature reports that work done to date has found no substantial antitumor effect of notch inhibitors.  There are no notch inhibitor therapies in clinical use at this time.

Consequences of Disrupted Notch Signaling in Bladder Cancer.

Molecular pathways: translational and therapeutic implications of the Notch signaling pathway in cancer.

NOTCH pathway inactivation promotes bladder cancer progression.

NOTCH Decoys That Selectively Block DLL/NOTCH or JAG/NOTCH Disrupt Angiogenesis by Unique Mechanisms to Inhibit Tumor Growth
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Changes in the regulation of the Notch signaling pathway are temporally correlated with regenerative failure in the mouse cochlea
.

Notch inhibitors for pulmonary arterial hypertension – SciBX Science Business Exchange

Notch inhibition reverses kidney failure – Nature

PARP Inhibitors

PARP Inhibitors (PARPi) are a promising group of drugs with a wide potential as sensitizers for chemotherapy and radiotherapy.

Hedgehog pathway inhibitors

The Hedgehog signaling pathway transmits signals to cells and tells them what kind of cells to turn into.  When an embryo develops cells must differentiate so the organism can have different organs and function as a multi-cellular organism.  Biologists name subtypes the Desert, Indian, and Sonic pathways. Even after the baby is born, there is still a Hedgehog signaling pathway.  In adults, the pathway sometimes becomes activated leading to (or somehow being associated with) the proliferation of malignant cells. The stem cells present in the body are converted to cancer cells.  Scientists are still trying to figure it all out, but there is evidence that activation of the Hedgehog pathway occurs in initiation and growth of several types of cancer, including basal cell carcinoma.

The oral drugs Sonidegib and Vismodegib are on the market and approved for basal cell carcinoma.  Glasdegib was approved in 2018 for acute myeloid leukemia.

Itraconazole has been used as an anti-fungal medication and scientists found it works in disrupting the hedgehog pathway.  It has therefore sparked interest by scientists who see an opportunity to repurpose it as a cancer medicine.  Clinical trials are underway to look into itraconazole for melanoma positive for the BRAF V600 mutation and for basal cell cancer.

Vismodegib

Sonidegib

Glasdegib

SignalTraducerInhibitors