Table 4.
Summary of clinical trials with PKC regulators
| Indication | Drug Reference | Proposed mechanism |
Outcome |
Company Comments |
|---|---|---|---|---|
| Congestive heart failure | Flosequinan156,157 | Non-selective ↓PKC |
Increased hospitalizations and mortality required early study termination | Withdrawn from clinical use |
| Coronary bypass grafting (preconditioning) | Volatile anesthetics161–165 | ↑PKCε | Reduction in troponin I levels, need for inotropic support, and prolonged hospitalization (>7days) | Sevoflurane and desflurane compared to propofol in moderate size studies. |
| Adenosine166–168 | ↑PKCε | Reduction in composite AMI, mortality, need for pressors postoperatively. | Requires validation in larger study | |
| Acadesine169,170,2 30 | ↑PKCε ↑AMPK* |
No reduction in death, AMI, or stroke | Reduced two year mortality in the small group of patients who had a post-operative AMI. | |
| Acute myocardial infarction Salvage | Adenosine171 | ↑PKCε | No reduction in composite endpoint of death and CHF | Reduced infarct size from 27% to 11% when given at 70 mcg/kg/min |
| Delcasertib172,173 | ↓PKCδ | No benefit when given intravenously | Positive biomarker trend when given to patients with TIMI 0/1 flow | |
| Bipolar Mania | Tamoxifen183–186 | Nonselective ↓PKC (at high dose) ER# inhibitor |
Several small studies show significant benefit in acute mania | High dose tamoxifen (80 mg/day) increases risk of thrombo-embolism, stroke, and uterine cancer |
| Oncology | Bryostatin121–134 | Nonselective ↑PKC |
Minimal to no benefit against a number of cancers. | Causes severe myalgias in >50% of patients. No ongoing studies. |
| Aprinocarsen135– 141 | ↓PKCα | Limited to no benefit against a number of cancers. | Development discontinued | |
| Enzastaurin142–148 | ↓PKCβ | Very rare to no objective responses against a number of cancers | Ongoing studies in brain malignancies | |
| Tamoxifen149–151 | Nonselective ↓PKC (at high dose) ER# inhibitor |
Limited to no benefit in malignant gliomas and hormone refractory prostate cancer | High dose tamoxifen (80 mg/day) increases risk of thromoembolism, stroke, and uterine cancer | |
| Midostaurin152,153 | Nonselective ↓PKC ↓FMS-like Tyrosine kinase 3 |
No effect in metastatic malignant melanoma. Decreased peripheral blasts in leukemia. | Leukemia trials being conducted. | |
| UCN-01154,155,231 | Nonselective ↓PKC ↓Chk1 |
No response in advanced renal cell cancer or ovarian cancer | Studied in combination with topotecan in ovarian cancer study | |
| Diabetic Retinopathy | Ruboxistaurin158, 174–177 | ↓PKCβ | Reduced sustained moderate vision loss in large studies | Under review by FDA for diabetic retinopathy |
| Diabetic Nephropathy | Ruboxistaurin179, 180 | ↓PKCβ | Failed to improve kidney outcomes | Studied as secondary outcome in large retinopathy trials |
| Diabetic Neuropathy | Ruboxistaurin181, 182 | ↓PKCβ | Mild decrease in symptoms | Small, short-term studies. Requires validation in larger study |
| Transplant Rejection | Sotrastaurin187,188 | Nonselective ↓PKC |
Marked increase in rejection | Rejection occurred when used in combination with mycophenolate |
*
AMP-activated protein kinase
#
estrogen receptor