Matrix metalloproteinase 13 inhibitors (Moffitt Cancer Center/Florida Atlantic University)

Several adverse events have been associated with atezolizumab (Genentech/Roche, Tecentriq) as seen in clin. trials, including fatigue, pruritus, pyrexia, rash, pneumonitis, hepatitis, colitis, and endocrine disorders.Furthermore, only few cases of acute kidney injury related to acute interstitial nephritis "(AIN) or tumor lysis syndrome have been reported".We present, to the best of our knowledge, the first cases of biopsy-proven glomerular thrombotic microangiopathy (TMA) after atezolizumab use in two patients with metastatic renal cell carcinoma (mRCC) cancers.Renal TMA or TMA-like lesion is a known antievascular endothelial growth factor (VEGF) therapy adverse event but lesser during intracavernosal injection (ICI) treatments 3-10. Furthermore, few cases of thrombotic thrombocytopenic purpura (TTP) have been associated with CPI treatment with an acquired TTP with ADAMTS 13 deficiency (ADAMTS 13 activity < 5%) associated with pos. ADAMTS 13 inhibitor. Although we can hypothesise that advanced malignant tumors can trigger hemolytic uremic syndrome (HUS) and/or thrombotic thrombocytopenic purpura itself, strikingly, the temporal parallel of initiation of checkpoint inhibitor and onset of TMAs within weeks is the common characteristic of our and the other reported cases.

Matrix metalloproteinase 13 (MMP‐13) activity has been correlated to breast cancer bone metastasis. It has been proposed that MMP‐13 contributes to bone metastasis through the promotion of osteoclastogenesis. To explore the mechanisms of MMP‐13 action, we previously described a highly efficacious and selective MMP‐13 inhibitor, RF036. Unfortunately, further pursuit of RF036 as a probe of MMP‐13 in vitro and in vivo activities was not practical due to the limited solubility and stability of the inhibitor. Our new study has explored replacing the RF036 backbone sulfur atom and terminal methyl group to create inhibitors with more favorable pharmacokinetic properties. One compound, designated inhibitor 3, in which the backbone sulfur and terminal methyl group of RF036 were replaced by nitrogen and oxetane, respectively, had comparable activity, selectivity, and membrane permeability to RF036, while exhibiting greatly enhanced solubility and stability. Inhibitor 3 effectively inhibited MMP‐13‐mediated osteoclastogenesis but spared collagenolysis, and thus represents a next‐generation MMP‐13 probe applicable for in vivo studies of breast cancer metastasis.