afuresertib (LAE002)

Treatment of cells with the AKT inhibitors MK2206 and GSK2110183 revealed that the PRKAA1 overexpression group was less sensitive to AKT inhibitors than the negative control group. Taken together, PRKAA1 can be used as a potential prognostic marker and new target for tumor immunotherapy.

P1/2, N=22, Active, not recruiting, Laekna Limited | Recruiting --> Active, not recruiting | N=167 --> 22

P1/2, N=49, Completed, Laekna Limited | Active, not recruiting --> Completed | N=74 --> 49 | Trial completion date: Oct 2024 --> Mar 2024

P2, N=150, Completed, Laekna Limited | Active, not recruiting --> Completed

P3, N=256, Recruiting, Laekna Limited | Active, not recruiting --> Recruiting | Phase classification: P1 --> P3 | N=20 --> 256 | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Apr 2023 --> Oct 2026

P2, N=141, Active, not recruiting, Laekna Limited | Trial completion date: Nov 2024 --> Jun 2024

P1, N=21, Completed, Laekna Limited | Recruiting --> Completed

Applying the ML approach to predict the drug response for each medication revealed an upstanding performance for SVM in predicting Afuresertib drug response (area under the curve [AUC] 0.875) using CIT, GAS2L3, STAG3L3, ATP2B4-mut, and IL15RA-mut as molecular features. Furthermore, the ANN algorithm using 9 mRNA characteristics demonstrated the highest prediction performance (AUC 0.780) in Gefitinib with CCL23-mut. This work extensively investigated the mRNA and mutation signatures associated with drug response in LUAD using a machine-learning approach and proposed a priority algorithm to predict drug response for different drugs.

Re-sensitization to cisplatin-induced cell death was achieved using clinically approved compounds aiming to restore p53 wild-type function (PRIMA1-Met), or inhibition of AKT-driven MAPK survival pathways (afuresertib), in both cases being partially due to ferroptosis induction. Consequently, active ferroptosis induction using the GPX4 inhibitor RSL3 proved superior in tumorselectively fighting MM cells. Due to high prevalence of the E285-cluster mutations in MM as well as in a variety of other tumor types, we conclude this cluster to serve an important function in tumor development and therapy and suggest new implications for ferroptosis induction in therapeutic applications fighting MM in particular and cancer in general.

P2, N=141, Active, not recruiting, Laekna Limited | Trial completion date: Sep 2023 --> Nov 2024

Conclusions The preliminary data from the combination therapy of afuresertib plus fulvestrant has shown promising efficacy with a well-tolerated safety profile in patients with HR+/HER2- LA/mBC who progressed on 1-2 prior lines of standard of care therapies. These results support further evaluation of this combination therapy in this patient population in an upcoming phase III study.

P1/2, N=167, Recruiting, Laekna Limited | Trial primary completion date: Aug 2023 --> Aug 2024

P2, N=141, Active, not recruiting, Laekna Limited | Recruiting --> Active, not recruiting

Finally, high-risk groups were more sensitive to MR-1220, GSK2110183 and temsirolimus, indicating that risk characteristics could predict drug sensitivity in TNBC patients to a certain extent. This study proposes an immunophenotype-based risk assessment model that provides a more accurate prognostic assessment tool for patients with TNBC and also predicts new potential compounds by performing machine learning algorithms.

P1, N=20, Active, not recruiting, Laekna LLC | Recruiting --> Active, not recruiting

Interestingly, afuresertib enhanced the antitumor efficacy of azeliragon in a xenograft mouse model. Collectively, our findings revealed previously unreported aspects of the drug azeliragon, and identified a novel combination strategy for the treatment of pancreatic cancer patients.

P1, N=20, Recruiting, Laekna LLC | Trial primary completion date: Jan 2023 --> Jun 2023

P1/2, N=74, Active, not recruiting, Laekna Limited | Recruiting --> Active, not recruiting

P1, N=20, Recruiting, Laekna LLC | Trial primary completion date: Sep 2022 --> Jan 2023

P2, N=141, Recruiting, Laekna Limited | Trial completion date: Jan 2023 --> Sep 2023 | Trial primary completion date: Jul 2022 --> May 2023

P1/2, N=74, Recruiting, Laekna Limited | Trial completion date: Oct 2022 --> Oct 2024 | Trial primary completion date: Sep 2022 --> Oct 2023

Additionally, Four agents, including ABT737, WIKI4, afuresertib, and GNE 317, were more sensitive in the high-risk group. The Eight-CTZFLs prognostic signature may be a helpful prognostic indicator and may help with medication selection for clear cell renal cell carcinoma.

More importantly, we found that afuresertib could reduce tumor volume and mass in EC rats through in vivo experiments. In conclusion, afuresertib may exert its antitumor effect by inhibiting the expression of PI3K and Akt-related proteins in rat tumor tissues.

P1/2, N=167, Recruiting, Laekna Limited | Not yet recruiting --> Recruiting

P1/2, N=167, Not yet recruiting, Laekna Limited

P1, N=20, Recruiting, Laekna LLC | Not yet recruiting --> Recruiting

Dual PI3K/mTOR (LY3023414, bimiralisib) and AKT inhibitors (ipatasertib, afuresertib) induced dose-dependent reductions in cell growth. However, mTOR-selective inhibitors (everolimus, rapamycin) alone did not exert cytotoxic effects. The MEK1/2 inhibitor trametinib did not impact proliferation even at the highest doses tested. Our data suggest that molecularly targeted strategies may be effective in PI3K/AKT/mTOR-activated ssRMS. Taken together, these data highlight the importance of utilizing patient-derived models to assess molecularly targetable treatments and their potential as future treatment options.

P1, N=20, Not yet recruiting, Laekna LLC | Initiation date: Sep 2021 --> Jan 2022

P1/2, N=74, Recruiting, Laekna Limited | Trial completion date: Oct 2021 --> Oct 2022 | Trial primary completion date: Sep 2021 --> Sep 2022

In particular, we demonstrate that treatment of MCC cells with Afuresertib led to the de-activation of mTOR and GSK3 pathway proteins while increasing the activation of pro-apoptotic pathways through the upregulation of p16 expression and phospho-modulation of the Bcl-2-associated death promoter. Overall, Afuresertib treatment led to significant and robust inhibition of MCC cell proliferation, thus raising intriguing questions regarding the potential efficacy of AKT inhibition for the future clinical management of MCCs.

In K562-FLT3 cells, a STAT5 inhibitor, pimozide, downregulated CD52 protein expression while an AKT inhibitor, afuresertib, did not affect CD52 expression. Taken together, our data suggested that genetically modified FLT3-ITD knock-in human myeloid leukemia K562 cells upregulated CD52 expression via activation of STAT5, and alemtuzumab showed an antitumor effect via induction of ADCC in K562-FLT3 cells. Our findings may allow establishment of a new therapeutic option, alemtuzumab, to treat leukemia with the FLT3-ITD mutation.

P1, N=20, Not yet recruiting, Laekna LLC

To better understand how these drugs exert their therapeutic effects at the molecular level, we combined chemoproteomic target affinity profiling using kinobeads and phosphoproteomics to analyze the five clinical AKT inhibitors AZD5363 (Capivasertib), GSK2110183 (Afuresertib), GSK690693, Ipatasertib, and MK-2206 in BT-474 breast cancer cells. These included CEP170 and FAM83H, suggesting a regulatory function of AKT in mitosis and cytoskeleton organization. In addition, a specific phosphorylation pattern on the ULK1-FIP200-ATG13-VAPB complex was found to determine the active state of ULK1, leading to elevated autophagy in response to AKT inhibition.

The present study demonstrated that curcumin had a stronger cytotoxic activity against AML cells compared with three other types of phytochemicals (epigallocatechin gallate, genistein and resveratrol). In the AML xenograft mouse model, curcumin and afuresertib synergistically suppressed the engraftment, proliferation and survival of AML cells. Collectively, the present study demonstrated that curcumin exerted anti‑AML roles by inactivating AKT and these findings may aid in the treatment of AML.

The reversal of the dual functions of ABC-transporter-mediated and AKT-activation-enhanced MDR through the inhibition or knockout of PI3K 110α or 110β promises to improve current strategies based on combined drug treatments to overcome MDR challenges.

P2, N=141, Recruiting, Laekna Limited | Not yet recruiting --> Recruiting

PF-04691502, a selective PI3K inhibitor, suppressed the augmented phosphorylation of Akt and its substrate FoxO3a. Treatment with afuresertib (a specific Akt inhibitor) in combination with bortezomib additively decreased FAM46C MM cell survival. Collectively, this study is the first to demonstrate that loss of FAM46C triggers the concomitant activation of PI3K-Akt signaling pathway, which might be a therapeutic target for MM with abnormalities in FAM46C gene.

Lenalidomide (Len) selectively binds to cereblon (CRBN), which mediates recruitment of specific substrates like IKZF1 to E3 ubiquitin ligase and subsequent degradation, resulting in downregulation of IRF-4 and c-Myc...We observed that ADCC activity of both daratumumab and elotuzumab against MM cells was enhanced in the presence of HDAC inhibitors, which was compatible with our previous data that HDAC inhibitors upregulated MICA mRNA expression via inhibition of IKZF1 (ASH2018 abstract #4435)...Afuresertib, an AKT inhibitor, suppressed GSK-3 phosphorylation (p-GSK-3) with or without ACY-1215, an HDAC inhibitor, leading to a substantial decrease of c-Myc (Figure 2)...Bortezomib, doxorubicin, and dexamethasone resistant MM cell lines were also sensitive to CUDC-907...Furthermore, CUDC-907 was effective on primary MM cells which were resistant to bortezomib and Len (Figure 5). Thus, dual inhibition of HDAC and AKT with or without monoclonal antibodies is a promising therapeutic approach to multi-drug resistant MM.