rupitasertib (DIACC3010) / EMD Serono, Evexta Bio - LARVOL DELTA

p70S6K as a Potential Anti-COVID-19 Target: Insights from Wet Bench and In Silico Studies. (PubMed, Cells) - "Meanwhile, our in silico investigations address the known off-target effects associated with M2698 by identifying a close analog called S34. In conclusion, this study presents novel and intriguing findings that could potentially lead to clinical applications with further investigations."

Journal • CNS Disorders • Infectious Disease • Inflammation • Novel Coronavirus Disease • Psychiatry • Respiratory Diseases • AKT2 • RPS6KB1

SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma. (PubMed, Sci Transl Med) - "To block pS6, we paired dasatinib with the S6K/AKT inhibitor M2698, which led to a marked reduction in pS6 in IDHm ICC cell lines and patient-derived organoids in vitro and substantial growth inhibition in ICC patient-derived xenografts in vivo. Together, these results elucidated the mechanism of action of dasatinib in IDHm ICC, revealed a signaling complex regulating S6K phosphorylation independent of mTOR, suggested markers for dasatinib sensitivity, and described a combination therapy for IDHm ICC that may be actionable in the clinic."

Journal • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • IDH1 • IDH2 • MAGI1 • PDZK1 • RPS6

Evexta Bio Reports Progress towards Clinical Development of Rupitasertib in Advanced Breast Cancer (GlobeNewswire) - P1 | N=101 | NCT01971515 | Sponsor: EMD Serono | "In a Phase 1 trial (Tsimberidou et al 2021) involving heavily pretreated patients with various solid tumors, including those with ESR1mt, rupitasertib was shown to have a favorable safety profile along with preliminary signs of efficacy...preclinical studies in ESR1mt breast cancer models have shown compelling synergistic effects of rupitasertib administered in combination with elacestrant. These data support the preliminary clinical efficacy observed in the Phase 1 study and warrant the development of rupitasertib in ESR1mt ER+ HER2- advanced breast cancer patients."

P1 data • Preclinical • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

Evexta Bio Reports Progress towards Clinical Development of Rupitasertib in Advanced Breast Cancer (GlobeNewswire) - "Following a Type B meeting held on March 13, 2024, the U.S. Food and Drug Administration (FDA) provided Evexta Bio with valuable input on various aspects of rupitasertib development, including CMC, preclinical and clinical topics, enabling the company to proceed with the Phase 2 study in advanced breast cancer...The Phase 2 trial is expected to start enrolling patients in Q4/2024. This Phase 2, open label study will evaluate the safety and efficacy of rupitasertib + elacestrant (ORSERDU) in patients with ER+ HER2- advanced breast cancer with detectable mutation/s of the estrogen receptor 1 gene (ESR1mt)."

FDA event • New P2 trial • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

p70S6K/Akt dual inhibitor DIACC3010 is efficacious in preclinical models of gastric cancer alone and in combination with trastuzumab. (PubMed, Sci Rep) - "Of the 21 HER2-negative PDX models, DIACC3010 significantly inhibited the growth of 38%. Altogether, these results provide a path forward to validate the potential biomarkers of DIACC3010 sensitivity in GC and support clinical evaluation of DIACC3010 monotherapy and combination with trastuzumab in patients with HER2- negative and positive advanced GCs, respectively."

Combination therapy • Journal • Preclinical • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • AKT1 • HER-2 • PIK3CA

DIACC3010, optimized inhibitor of S6 kinase, combined with endocrine therapy, has potent antitumor activity in treatment-resistant ER-positive HER2-negative metastatic breast cancer (AACR 2023) - P1 | "We performed exploratory correlative analyses of the phase 1 trial in ER+ HER2-negative MBC patients in addition to nonclinical experiments to evaluate its role in the CDK4/6 and endocrine therapy (ET) resistant setting. DIACC3010 was evaluated as monotherapy, or combined with either trastuzumab or tamoxifen, in a multicenter phase 1 trial that accrued 101 patients with advanced/refractory solid tumors (Tsimberidou et al, J Hematol Oncol 2021 14(1):127). Exploratory analyses from the phase 1 trial, along with nonclinical efficacy in PDX models, demonstrate that DIACC3010 may have antitumor activity in MBC patients with ET resistance. Experiments are underway to assess nonclinical efficacy of DIACC3010 combination with elacestrant or CDK4/6 inhibitors in various models of ER+ MBC, including ET resistant."

Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • AKT1 • AKT2 • ER • HER-2 • RPS6

Diaccurate Announces Updated Data on its Novel PAM Pathway Inhibitor DIACC3010 in Patients with ER+ HER2- Metastatic Breast Cancer to be Presented at AACR 2023 (GlobeNewswire) - "DIACCURATE...announced that it has been selected to present new nonclinical efficacy and clinical exploratory correlative analyses of its lead compound DIACC3010 in metastatic ER+ HER2- breast cancer in a poster at the American Association of Cancer Research (AACR) Annual Meeting 2023....The communication features an exploratory correlative analysis from DIACC3010 Phase 1 study focused on the combination cohort of DIACC3010 and tamoxifen, in highly refractory ER+ HER2- metastatic breast cancer patients. The patients who had detectable mutations in the ESR1 gene achieved median progression-free survival of 5.6 months, as compared to only 2.6 months in patients with no detectable ESR1 mutations. In addition, nonclinical efficacy results of DIACC3010 in combination with the SERM tamoxifen and the SERD elacestrant were performed. Combinations of DIACC3010 with CDK4/6 inhibitors...in various mouse models of ER+ HER2- breast cancer, will also be disclosed."

P1 data • Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology. (PubMed, Cell Biosci) - "Our data elucidate the incidence and mechanisms of psychiatric AEs in patients treated with PI3K/AKT/mTOR inhibitors and emphasize the need for careful monitoring."

Journal • CNS Disorders • CNS Tumor • Depression • Insomnia • Mental Retardation • Mood Disorders • Oncology • Psychiatry • Schizophrenia • Sleep Disorder • AKT3

Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer. (PubMed, J Hematol Oncol) - P1 | "M2698 was well tolerated. Combined with trastuzumab or tamoxifen, M2698 demonstrated antitumor activity in patients with advanced breast cancer resistant to multiple standard therapies, suggesting that it could overcome treatment resistance. Trial registration ClinicalTrials.gov, NCT01971515. Registered October 23, 2013."

Clinical • Journal • P1 data • Breast Cancer • Fatigue • Gastrointestinal Disorder • Oncology • Solid Tumor • AKT2 • EGFR • KRAS

Identification of Clinical Candidate M2698, a Dual p70S6K and Akt Inhibitor, for Treatment of PAM Pathway-Altered Cancers. (PubMed, J Med Chem) - "Through the screening of in-house proprietary kinase library, 4-benzylamino-quinazoline-8-carboxylic acid amide 1 stood out, with sub-micromolar p70S6k biochemical activity, as the starting point for a structurally enabled p70S6K/Akt dual inhibitor program that led to the discovery of M2698, a dual p70S6k/Akt inhibitor. M2698 is kinase selective, possesses favorable physical, chemical, and DMPK profiles, is orally available and well tolerated, and displayed tumor control in multiple in vivo studies of PAM pathway-driven tumors."

Clinical • Journal • Oncology

Surface protein marker and single cell gene expression profiling of individual tumor cells dissociated from small cell lung cancer pdx mouse models can be correlated with in vivo sensitivity to the p70S6K/AKT1/3 inhibitor M2698 (AACR 2019) - "In one case, the ratio of two populations shifted concurrently with growth differences, raising the possibility of a dynamic relationship between this equilibrium and the growth stage. Overall, our workflow may provide tools for sample characterization, quality control and elucidation of cellular response markers to varying selective pressures, such as drug challenges."