Other Signal Transduction Inhibitors

The body has many complex biochemical processes.  Many involve transmission of signals from cell to cell or within a cell.  These signals can involve tissue growth, maintaining an organism-wide state (e.g. sleep), or a response to an external stimulus. Cascades of reactions, especially protein phosphorylation facilitated by kinase enzymes, termed signal transduction are key to this control of the body. Cancer growth takes advantage of signal transduction pathways.  Scientists have found some (not all) of the ways the cancer growth signal propagates through the body.  Proteins that detect the biochemical signals are called “receptors”.

Ways to interfere with cancer include inhibiting the kinases (and hence stopping or slowing the signal transduction), or blocking the receptors with other chemicals (and hence blocking the effect of the signal.)

Signal Transduction Inhibitors are medicines that block chemical signals from cell to cell. These signals are part of often-complex biochemical pathways that produce a cellular response. Most of the signal transduction inhibitors in clinical use are kinase inhibitors. Other types find uses in cancer therapy, too.

Proteasome inhibitors

Proteasomes are physiological micostructures that are part of the body’s waste management system. The Ubiquitin Proteasome Pathway (UPP)  breaks down old and unneeded proteins that the cells need to be rid of.   In normal healthy cells the pathway is part of the homeostasis that allows cells to die.  Cancer cells operate at higher metabolic rates than healthy cells do and subsequently produce more proteins for disposal.  Malignant cells are consequently more at risk from interruptions to the proteasome.  Compounds that stop or slow the action of the proteasome are called proteasome 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 multiple myeloma, mantle-cell lymphoma (MCL) and amyloidosis.  They often produce good results but the doctors report that relapses are common as the cancer seems to develop resistance.

Proteasome inhibitors have names that end in “zomib”

Ixazomib
Carfilzomib
Bortezomib

Other proteasomes inhibitors under investigation include oprozomib, delanzomib, and marizomib (aka salinosporamide)

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, particularly in the G1 phase of and at the G2/M transition.   The series of reactions functions as a signal – it is referred to as signal transduction. Parts of this pathway are in involved in 70 percent of cancers.  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 PI3K inhibitors in the laboratory. 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 PI3K inhibitors.

PI3K Inhibitors

Phosphoinositide 3-kinase enzymes 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 signal transducers and work (among elsewhere) in transmission of signals across the cell membrane.  They are particularly important in the growth of same cancers and biochemists classify them as part of the PI3K/AKT/mTOR pathway.  Many enzymes could be considered PIK3 ones, and biologists have further divided them into four classes: PI3K I, PI3K II, and PI3K III with PI3K IV sometimes included although molecules in this class are serine/threonine kinases.  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 many types of cancer.

Scientists have found small molecule drugs that can stop the action of the enzymes. These are called phosphatidylinositol 3-kinase inhibitors or phosphoinositide 3-kinase inhibitors but almost always designated by the abbreviation PI3K inhibitors.  (Sometimes misidentified as P13K inhibitors.)

Only five 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. Umbralisib, Idelalisib, Copanlisib and Duvelisib were all approved for lymphoma. Alpelisib was approved for breast cancer treatment.  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.

Writing in 2019, a pharmaceutical industry analyst noted the dearth of research in this class, saying “broadly acting PI3k inhibitors have disappointed”.

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 inhibitors 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.

BCL-2 Inhibitors

Bcl-2 stands for B-cell lymphoma 2; this is a regulatory protein that sometimes goes wrong in cancerous cells. Inhibiting this protein is one strategy for attacking cancer.

Only one BCL-2 inhibitor, Venetoclax, has been approved for cancer treatment.

NTRK inhibitors aka TRK Inhibitors

NTRK stands for neurotrophin receptor kinase.  NTRK1, NTRK2 or NTRK3 encode the neurotrophin receptors TRKA, TRKB and TRKC.  These drive tumor growth in certain cancers. Inhibiting them has been an area of interest. These drugs might target the receptors or the consequence of a fusion of these genes with other genes.  Larotrectinib and entrectinib are considered first-generation NTRK inhibitors. Second-generation compounds are in development, including LOXO-195 and TPX-0005.  Crizotinib and cabozantinib produce some off-target inhibition of NTRK, but they are not classified primarily as NTRK inhibitors.

RET Inhibitors

RET stands for Rearranged during Transfection. This protein is “a transmembrane tyrosine kinase expressed in central and peripheral nervous system.

Some cancer patients have mutations in this protein; the mutation drives growth of malignancies. Anti-cancer drugs that block this mutated protein might benefit patients with the mutation. Pralsetinib and selpercatinib primarily act through this route. Sunitinib, sorafenib, vandetanib, and ponatinib are sometimes considered RET Inhibitors although they also act by other mechanisms.

PARP Inhibitors

PARP Inhibitors (Poly (ADP-ribose) polymerase inhibitors, or PARPi) interfere with the cell’s DNA repair and hence cause cell death.  Four have been approved by the FDA.  See page on PARPi.

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 give the names Desert, Indian, and Sonic pathways to subtypes of the Hedgehog pathway. Even after the baby is born, the Hedgehog signaling pathway exists. 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 of researchers who see an opportunity to repurpose it as a cancer medicine.  Clinical trials are underway to look into itraconazole for treatment of melanoma that tests positive for the BRAF V600 mutation and for basal cell cancer.

Vismodegib

Sonidegib

Glasdegib

Selective inhibitors of nuclear export

Exportin 1 is a protein scientists have discovered plays an important part in cell function.  It’s involved in the movement of RNA from the nucleus to the protoplasm. Chemicals called selective inhibitors of nuclear export (SINE) can stop or slow the action of exportin 1. Several SINE compounds have been investigated as cancer therapies, but only one, selinexor, has been approved for clinical use.

PDF List of Signal Transducer Inhibitors