torkinib (PP242)

Inhibition of CK1α using short hairpin RNA (shRNA) and treatment of a CK1α inhibitor or an mTOR inhibitor, TORKinib, resulted in decreased β-TrCP interaction with LT, increased LT expression, and enhanced MCPyV replication...Therefore, cellular kinase pathways are indispensable for governing MCPyV polyomavirus infection and life cycle in coordinating with the immunosuppression environment at disease onset. Understanding the regulation mechanisms of MCPyV replication by viral and cellular factors will guide proper prevention strategies with targeted inhibitors for MCPyV-associated Merkel cell carcinoma (MCC) patients, who currently lack therapies.

Targeting HSP90 and mTOR has the potential to suppress breast cancer cell growth and progression by disrupting AKT signaling and inhibiting F-actin polymerization. This combination treatment may hold promise as a therapeutic strategy for breast cancer treatment that ameliorates adverse effects of a single treatment.

In this research, we show that the long non-coding RNA MLLT4 antisense RNA 1 (lncRNA MLLT4-AS1) is induced by the MTORC inhibitor PP242 and rapamycin in cervical cells. Mechanically, MLLT4-AS1 was associated with the myosin-9 protein, which further promoted the transcription activity of the ATG14 gene. In conclusion, we demonstrated that MLLT4-AS1 acts as a potential tumor suppressor in cervical cancer by inducing autophagy, and H3K27ac modification-induced upregulation of MLLT4-AS1 could cause autophagy by associating with myosin-9 and promoting ATG14 transcription.

In addition, we confirmed that combination treatment with the mTORC2 inhibitor PP242 and the PARP inhibitor olaparib synergistically inhibited pancreatic cancer growth in vivo. Thus, this study provides a novel target and strategy for optimizing PARP inhibitor efficiency in pancreatic cancers.

In a selection of 166 compounds we showed that inhibitors of ATR and WEE1 were cytotoxic against a panel of OCCC cell lines. These two drugs are already in other clinical trials, making them ideal candidates for treatment of OCCC.

The following inhibitors were used: protein kinase inhibitors such as AKT-MK-2206, MEK-AS-703026, mTOR-everolimus and Torkinib, as well as dual PI3K and mTOR inhibitor-BEZ-235 and Omipalisib, and mTOR1/2-OSI-027 inhibitor in single-mode and their combinations with MEK1/2 kinase inhibitor AS-703026. There is a need for research on the search for new therapeutic strategies aimed at particular groups of patients. Effect of three generations of mTOR kinase inhibitors on caspase-3 activity, apoptosis and proliferation in melanoma cell lines.

Here we explored the role of the mTOR pathway in the regulation of stem cells of GBM by treating them with inhibitors of canonical PI3K/AKT/mTOR pathways such as rapamycin (mTORC1 inhibitor), PP242 (ATP binding mTORC1/2 inhibitor), LY294002 (PI3K inhibitor), and MAPK inhibitor, U0126...Treatment with novel small molecule inhibitors of mTORC1/2 demonstrated that Torin1 and Torin2 suppressed the proliferation of GBM CSC, while XL388 was less effective...Torin2 was able to eradicate tumor cells. In conclusion, Torin2 effectively targeted CSCs of GBM by halting self-renewal and inhibiting cell proliferation, underscoring the use of Torin2 in the treatment of GBM.

Thus, the bromodomain inhibitor RVX-208 significantly augmented the therapeutic effects of the dual mTORC1/2 inhibitors, OSI-027 and PP242, both in vitro and in a human xenograft murine model. While single RVX-208 treatment induces apoptosis and a single mTORC1/2 inhibitor induces macropinocytosis, their combined treatment led to necroptosis-mediated cell death. These data suggest that combined treatment with drugs targeting BRD4 and mTORC1/2 may be an effective therapeutic intervention for drug-resistant RMS.

Thus, the combination of PP242 and metformin completely blocked the activity of both mTORC1 and mTORC2 kinase. This study suggests that this combination could be a more effective strategy for the treatment of CRC.

In present study, RCC cell lines (UMRC6, 786-0 and UOK121) were treated with NVP-BEZ235, PP242 or Rapamycin, an mTOR complex 1 (mTORC1)-specific inhibitor. We conclude that besides PI3K/Akt/mTOR signaling, NVP-BEZ235, and PP242 simultaneously target TAK1-dependent pathways in RCC cells. Notably, these effects were more marked in the presence of NVP-BEZ235 than PP242, indicating the potential application of NVP-BEZ235 in combination therapy for RCC.

Our findings demonstrate that PP242 enhances the anti-tumor activity of SFN by blocking SFN-induced activation of Akt/mTOR pathway in ESCC, which provides a rationale for treating ESCC using SFN combined with Akt/mTOR pathway inhibitors.

Treatment of mTOR inhibitor PP242 with PTEN/SCAPΔL mice significantly attenuated liver injury and ER stress . The excessively strong and broad lipogenesis inhibition was counterproductive for NASH therapy, which will have important clinical implications in NASH treatment .

We revealed that the combined application of CTX and PP242 can inhibit tumor growth and proliferation by inhibiting the phosphorylation of key molecules in EGFR downstream MEK-ERK and MEK 4/7 (MKK)-c-Jun N-terminal kinase (JNK) signaling pathways in BRAF wild-type CRC cells. In addition, we found that in BRAF mutant CRC cells, the monotherapy of PP242 resulted in negative feedback increased EGFR phosphorylation rates, accompanied by significant up-regulation of downstream MEK and ERK phosphorylation.

The RIST treatment protocol has a multimodal metronomic therapy design combining molecular-targeted drugs (Rapamycin and Dasatinib) with chemotherapy backbone (Irinotecan and Temozolomide), which is currently verified in a phase II clinical trial (NCT01467986)...By comparing the IC values of Torin-1, Torin-2, AZD3147 and PP242 we established that only Torin-2 inhibited cell viability of all three MycN-amplified neuroblastoma cell lines tested at nanomolar concentration...However, at this point we cannot rule out that Torin-2 has increased toxicity due to its potency in more complex systems. Nonetheless, our results suggest that including Torin-2 as a substitute for Rapamycin in the RIST protocol may represent a valid option to be evaluated in prospective clinical trials for relapsed or treatment-refractory high-risk neuroblastoma.

Noteworthy, knocking-down stably RICTOR significantly suppresses RAD001-induced feedback activation of AKT/PRAS40 signaling, and enhances inhibition efficacy of PP242 on the phosphorylation of AKT and PRAS40, thus potentiates the antitumor effect of RAD001 and PP242 both in vitro and in vivo. Our findings highlight that selective targeting mTORC2 could be a promising therapeutic strategy for future treatment of ESCC.

Treatment with pan-mTOR inhibitor PP242 diminishes DNA damage-induced γH2AX and BRCA1 foci formation...These data suggest that mTOR signaling is required for BRCA1 response to DNA damage and breast cancer cells lacking BRCA1 are more sensitive to pan-mTOR inhibition. This work suggests chemotherapeutic strategies using mTOR inhibitors could be tailored for patients that lack functional BRCA1.