nuvisertib (TP-3654)

We then explored the effects of the selective PIM1 inhibitor TP-3654 on fibrosis...Downregulation of PIM1 expression in fibroblasts using drugs or siRNA leads to decreased ENO1 expression, concurrent with AKT phosphorylation reduction and suppressor of mothers against decapentaplegic (Smad)2/3 dephosphorylation within the TGF-β classical pathway. In summary, PIM1 might be an important target gene for future skeletal muscle atrophy treatments.

Repurposing FDA approved drugs with off-target autophagy inhibition such as chloroquine/hydroxychloroquine (CQ, HCQ) has produced modest anticancer activity in clinical trials, due in part, to a failure to define predictive biomarkers that enable the selection of patients that best respond to this treatment strategy. Inhibition of autophagy with CQ synergistically enhanced the in vitro and in vivo anticancer activity of TP-3654. Our findings identify REDD1 as a novel determinant of the sensitivity of RCC cells to autophagy inhibition and support further investigation of PIM kinase inhibition as a precision strategy to drive sensitivity to autophagy-targeted therapies through REDD1 upregulation.

P1/2, N=240, Recruiting, Sumitomo Pharma America, Inc. | N=80 --> 240 | Trial completion date: Feb 2025 --> Apr 2030 | Trial primary completion date: Dec 2024 --> Apr 2027

P1, N=12, Completed, Sumitomo Pharma America, Inc.

Cytotoxicity, apoptosis and protein expression and turnover were measured in FLT3-ITD-expressing cell lines and AML patient blasts treated with the FLT3 inhibitor gilteritinib and/or the Pim inhibitors AZD1208 or TP-3654. The data are consistent with c-Myc T58 and Mcl-1 S159 phosphorylation by activated GSK-3β as the mechanism of action of gilteritinib and Pim inhibitor combination treatment, further supporting GSK-3β activation as a therapeutic strategy in FLT3-ITD AML.  .

P1/2, N=80, Recruiting, Sumitomo Pharma America, Inc.

In this study, we evaluate the effect of the novel multikinase PIM/PI3K/mTOR inhibitor, AUM302, and commercially available PIM inhibitor, TP-3654. Significantly, AUM302 had a strong impact on the viability of gemcitabine-resistant PDAC cells. Taken together, these results demonstrate that AUM302 exhibits antitumor activity in human PDAC cells and thus has the potential to be an effective drug for PDAC therapy.

In preclinical studies, TP-3654 alone and in combination with ruxolitinib showed spleen size and bone marrow (BM) fibrosis reduction in murine MF models. This preliminary data of TP-3654 in relapsed/refractory MF pts showed early signs of clinical activity including spleen volume reduction, TSS improvement, and correlating cytokine reductions. TP-3654 is well tolerated with limited myelosuppressive adverse events. Enrollment is ongoing as monotherapy and current data support the development of TP-3654 in combination with JAK inhibitors given the preliminary clinical activity and minimal cytopenia.

Preliminary cytokine data showed that TP-3654 monotherapy may prompt early cytokine changes that may correlate with symptoms response. In addition, preliminary data of TP-3654 in relapsed/refractory MF patients showed SVR, TSS improvement, and BM fibrosis reduction. In the dose ranges evaluated to date, TP-3654 has been well tolerated with no myelosuppressive TRAEs.

In this study, we discovered that by attenuating the drug transport function of ABCG2, TP-3654 resensitizes ABCG2-overexpressing multidrug-resistant cancer cells to cytotoxic ABCG2 substrate drugs topotecan, SN-38 and mitoxantrone. Moreover, our results indicate that ABCG2 does not mediate resistance to TP-3654 and may not play a major role in the induction of resistance to TP-3654 in cancer patients. Taken together, our findings reveal that TP-3654 is a selective, potent modulator of ABCG2 drug efflux function that may offer an additional combination therapy option for the treatment of multidrug-resistant cancers.