AR-13503 is an active metabolite of Netarsudil

Sotrastaurin, an orally-active, first-in-class immunomodulator, is under development by Novartis for the treatment of uveal melanoma and diffuse-large B-cell lymphoma. Sotrastaurin is a low molecular mass synthetic compound that potently inhibits the PKC α, β and the θ isoforms resulting in selective NF-κB inactivation. Sotrastaurin is a potent and selective pan-PKC inhibitor, mostly for PKCθ with Ki of 0.22 nM in a cell-free assay. Inhibition of PKC beta in B-cells results in prevention of NF-kB-mediated signaling and down regulation of NF-kB target genes. This may eventually lead to an induction of G1 cell cycle arrest and tumor cell apoptosis in susceptible tumor cells. This agent may act synergistically with other chemotherapeutic agents. PKC, a family of serine/threonine protein kinases overexpressed in certain types of cancer cells, is involved in cell differentiation, mitogenesis, inflammation, and the activation and survival of lymphocytes. Sotrastaurin is currently in phase II trials by Novartis for the treatment of large B-cell lymphoma and uveal melanoma. Sotrastaurin was in Phase II of clinical development for the prevention of acute rejection after solid organ transplantation and psoriasis, but this reseach had being discontinued.

Safingol, the synthetic L-threo-stereoisomer of endogenous (D-erythro-) sphinganine, is an inhibitor of protein kinase C and sphingosine kinase in vitro, and in some cell types has been implicated in ceramide generation and induction of apoptosis. Safingol inhibits enzymatic activity and 3H-phorbol dibutyrate binding of purified rat brain PKC (IC50 = 37.5 uM and 31uM, respectively). Inhibits human PKCα, the major overexpressed isoenzyme in MCF-7 DOXR cells (IC50 = 40 uM). Safingol enhances the cytotoxic effect of the chemotherapeutic agent Mitomycin C (MMC) in gastric cancer cells by promoting drug-induced apoptosis. Safingol is an inhibitor of SphK (Sphingosine kinase). Safingol has been shown to act synergistically with other chemotherapeutic agents and may potentiate chemotherapy drug-induced apoptosis in vitro and in vivo.

Staurosporine is an alkaloid isolated from the culture broth of Streptomyces staurosporesa. It exerts antimicrobial, hypotensive, and cytotoxic activity. The main biological activity of staurosporine is the inhibition of protein kinases through the prevention of ATP binding to the kinase. This is achieved through the stronger affinity of staurosporine to the ATP-binding site on the kinase. Staurosporine is a prototypical ATP-competitive kinase inhibitor in that it binds to many kinases with high affinity, though with little selectivity. It is a potent, cell permeable protein kinase C inhibitor with an IC50 of 0.7 nM. At higher concentration (1-20 nM), staurosporine also inhibits other kinases such as PKA, PKG, CAMKII and Myosin light chain kinase (MLCK). At 50-100 nM, it is a functional neurotrophin agonist, promoting neurite outgrowth in neuroblastoma, pheochromocytoma and brain primary neuronal cultures. At 0.2- 1 uM, staurosporine induces cell apoptosis. Staurosporine is also a potent GSK-3β inhibitor with a reported IC50 value of 15 nM. In research, staurosporine is used to induce apoptosis. It has been found that one way in which staurosporine induces apoptosis is by activating caspase-3. Staurosporine was discovered to have biological activities ranging from anti-fungal to anti-hypertensive. The interest in these activities resulted in a large investigative effort in chemistry and biology and the discovery of the potential for anti-cancer treatment. Staurosporine induces apoptosis by multiple pathways and that the inhibition of more than one kinase is responsible for its potent activity. Because the mechanism of action of staurosporine is distinct from traditional anticancer drugs, this may warrant further preclinical evaluations of the antitumor potential of new staurosporine derivatives either alone or in combination with death ligands or conventional chemotherapeutic drugs.

Rottlerin is a principal phenolic compound of the Kamala plant Mallotus philippinensis. It was thought to be a selective inhibitor of PKCδ (protein kinase Cδ) (IC50=3-6 uM). It also inhibits PKCα, PKCβ, PKCγ, PKCε, PKCη, PKCζ and eEF2K (CaMK III) (IC50 = 5.3 uM). In HT1080 human fibrosarcoma cells, rottlerin induces apoptosis and autophagy via a PKCδ-independent pathway. When tested on HERG channels, rottlerin increased both step and tail HERG current by leftward shifting the voltage and dependence of HERG activation and slowing channel deactivation. Rottlerin is an inhibitor of Chk2, MAPKAPK-2, Pim-3, PKCλ, PKCθ, Plk, PRAK, SRPK1 and an activator of AMPK and HERG. There have been a number of studies published with evidence against the role of Rotterlin as a specific PKCδ inhibitor.

AR-13503 is an active metabolite of Netarsudil

AR-13503 is an active metabolite of Netarsudil

AR-13503 is an active metabolite of Netarsudil

Sotrastaurin, an orally-active, first-in-class immunomodulator, is under development by Novartis for the treatment of uveal melanoma and diffuse-large B-cell lymphoma. Sotrastaurin is a low molecular mass synthetic compound that potently inhibits the PKC α, β and the θ isoforms resulting in selective NF-κB inactivation. Sotrastaurin is a potent and selective pan-PKC inhibitor, mostly for PKCθ with Ki of 0.22 nM in a cell-free assay. Inhibition of PKC beta in B-cells results in prevention of NF-kB-mediated signaling and down regulation of NF-kB target genes. This may eventually lead to an induction of G1 cell cycle arrest and tumor cell apoptosis in susceptible tumor cells. This agent may act synergistically with other chemotherapeutic agents. PKC, a family of serine/threonine protein kinases overexpressed in certain types of cancer cells, is involved in cell differentiation, mitogenesis, inflammation, and the activation and survival of lymphocytes. Sotrastaurin is currently in phase II trials by Novartis for the treatment of large B-cell lymphoma and uveal melanoma. Sotrastaurin was in Phase II of clinical development for the prevention of acute rejection after solid organ transplantation and psoriasis, but this reseach had being discontinued.

Safingol, the synthetic L-threo-stereoisomer of endogenous (D-erythro-) sphinganine, is an inhibitor of protein kinase C and sphingosine kinase in vitro, and in some cell types has been implicated in ceramide generation and induction of apoptosis. Safingol inhibits enzymatic activity and 3H-phorbol dibutyrate binding of purified rat brain PKC (IC50 = 37.5 uM and 31uM, respectively). Inhibits human PKCα, the major overexpressed isoenzyme in MCF-7 DOXR cells (IC50 = 40 uM). Safingol enhances the cytotoxic effect of the chemotherapeutic agent Mitomycin C (MMC) in gastric cancer cells by promoting drug-induced apoptosis. Safingol is an inhibitor of SphK (Sphingosine kinase). Safingol has been shown to act synergistically with other chemotherapeutic agents and may potentiate chemotherapy drug-induced apoptosis in vitro and in vivo.