Akt-1 inhibitors(Serine/threonine-protein kinase AKT inhibitors), Akt-3 inhibitors(Serine/threonine-protein kinase AKT3 inhibitors), RSK inhibitors(Ribosomal protein S6 kinase inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersSkin and Musculoskeletal Diseases+ [2]

Active Indication

ER-positive/HER2-negative Breast CancerStomach CancerGlioblastoma Multiforme+ [1]

Inactive Indication-

Originator Organization

Diaccurate SAStartup

Active Organization

Diaccurate SAStartupMerck KGaA

Inactive Organization

EMD Serono, Inc.

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

Structure

Molecular FormulaC21H19ClF3N5O

InChIKeyHXAUJHZZPCBFPN-QGZVFWFLSA-N

CAS Registry1379545-95-5

Clinical Trials associated with Rupitasertib

NCT01971515 / CompletedPhase 1

A Phase I, First-in-Human, Dose Escalation Trial of MSC2363318A, a Dual p70S6K/Akt Inhibitor, in Subjects With Advanced Malignancies

This is a Phase 1, first-in-human, open-label, non-randomized, dose escalation, trial to explore the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and clinical activity signals of MSC2363318A.

Start Date13 Dec 2013

Sponsor / Collaborator

EMD Serono, Inc.

100 Clinical Results associated with Rupitasertib

100 Translational Medicine associated with Rupitasertib

100 Patents (Medical) associated with Rupitasertib

Literatures (Medical) associated with Rupitasertib

15 May 2024·Science Translational Medicine

SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma

Article

Author: Kenerson, Heidi L. ; Lampano, Aaron E. ; Bridgwater, Caroline M. ; Sokolov, David ; Yu, Angela ; Lampe, Paul D. ; Kathiresan, Meena ; Yáñez-Bartolomé, Mariana ; Sullivan, Lucas B. ; Saha, Supriya K. ; Macarulla, Teresa ; Haas, Wilhelm ; Kugel, Sita ; Yeung, Raymond S. ; Tian, Tian V. ; Cooper, Jonathan A. ; Hulahan, Taylor S. ; Luk, Iris S. ; Boukhali, Myriam ; Yamamoto, Naomi ; Engstrom, Ian A. ; Boila, Liberalis D.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive bile duct malignancy that frequently exhibits isocitrate dehydrogenase ( IDH1/IDH2 ) mutations. Mutant IDH (IDHm) ICC is dependent on SRC kinase for growth and survival and is hypersensitive to inhibition by dasatinib, but the molecular mechanism underlying this sensitivity is unclear. We found that dasatinib reduced p70 S6 kinase (S6K) and ribosomal protein S6 (S6), leading to substantial reductions in cell size and de novo protein synthesis. Using an unbiased phosphoproteomic screen, we identified membrane-associated guanylate kinase, WW, and PDZ domain containing 1 (MAGI1) as an SRC substrate in IDHm ICC. Biochemical and functional assays further showed that SRC inhibits a latent tumor-suppressing function of the MAGI1–protein phosphatase 2A (PP2A) complex to activate S6K/S6 signaling in IDHm ICC. Inhibiting SRC led to activation and increased access of PP2A to dephosphorylate S6K, resulting in cell death. Evidence from patient tissue and cell line models revealed that both intrinsic and extrinsic resistance to dasatinib is due to increased phospho-S6 (pS6). 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.

01 Dec 2022·Cell and BioscienceQ3 · BIOLOGY

AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology

Q3 · BIOLOGY

ArticleOA

Author: Shaw, Jamie ; Armen, Roger S ; Skliris, Antonis ; Pan, Jen Q ; Cottrell, Jeffrey R ; Tsichlis, Philip N ; Tsimberidou, Apostolia-Maria ; Hering, Ursula ; Chan, Tung On ; Vo, Henry Hiep ; Valentine, Alan

Abstract:

Background:

Changes in the expression and activity of the AKT oncogene play an important role in psychiatric disease. We present translational data assessing the role of AKT in psychiatric symptoms.

Methods:

(1) We assessed the protein activity of an AKT3 mutant harboring a PH domain mutation (Q60H) detected in a patient with schizophrenia, the corresponding AKT1 mutant (Q61H), and wild-type AKT1 and AKT3 transduced in AKT-null mouse fibroblasts and modeled the Q61H mutation onto the crystal structure of the Akt1 PH domain. (2) We analyzed the results of earlier genome-wide association studies to determine the distribution of schizophrenia-associated single-nucleotide polymorphisms (SNPs) in the AKT3 gene. (3) We analyzed the psychiatric adverse events (AEs) of patients treated with M2698 (p70S6K/AKT1/AKT3 inhibitor) and with other PI3K/AKT/mTOR pathway inhibitors.

Results:

(1) Proteins encoded by AKT3 (AKT3Q60H) and AKT1 (AKT1Q61H) mutants had lower kinase activity than those encoded by wild-type AKT3 and AKT1, respectively. Molecular modeling of the AKT1-Q61H mutant suggested conformational changes that may reduce the binding of D3-phosphorylated phosphoinositides to the PH domain. (2) We identified multiple SNPs in the AKT3 gene that were strongly associated with schizophrenia (p < 0.5 × 10–8). (3) Psychiatric AEs, mostly insomnia, anxiety, and depression, were noted in 29% of patients treated with M2698. In randomized studies, their incidence was higher in PI3K/AKT/mTOR inhibitor arms compared with placebo arms. All psychiatric AEs were reversible.

Conclusions:

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.

01 Dec 2021·Journal of hematology & oncologyQ1 · MEDICINE

Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer

Q1 · MEDICINE

ArticleOA

Author: Lopes, Gilberto ; Verschraegen, Claire ; Park, Haeseong ; Nemunaitis, John ; Ellers-Lenz, Barbara ; Mita, Monica ; Xiong, Wenyuan ; Sarantopoulos, John ; Juric, Dejan ; Shaw, Jamie V ; Tian, Hui ; Tsimberidou, Apostolia-Maria ; Weise, Amy M ; Kaleta, Remigiusz ; Kurzrock, Razelle

Abstract:

Background:

The PI3K/AKT/mTOR (PAM) pathway is a key regulator of tumor therapy resistance. We investigated M2698, an oral p70S6K/AKT dual inhibitor, in patients with advanced cancer who failed standard therapies.

Methods:

M2698 was administered as monotherapy (escalation, 15–380 mg daily; food effect cohort, 240–320 mg daily) and combined with trastuzumab or tamoxifen.

Results:

Overall, 101 patients were treated (M2698, n = 62; M2698/trastuzumab, n = 13; M2698/tamoxifen, n = 26). Patients were predominantly aged < 65 years, were female, had performance status 1 and were heavily pretreated. There was a dose- and concentration-dependent inhibition of pS6 levels in peripheral blood mononuclear cells and tumor tissue. M2698 was well tolerated; the most common treatment-emergent adverse events were gastrointestinal, abnormal dreams and fatigue (serious, attributed to M2698: monotherapy, 8.1%; M2698/trastuzumab, 7.7%; M2698/tamoxifen, 11.5% of patients). The recommended phase 2 doses of M2698 were 240 mg QD (monotherapy), 160 mg QD (M2698/trastuzumab) and 160 mg QD/240 mg intermittent regimen (M2698/tamoxifen). In the monotherapy cohort, 27.4% of patients had stable disease at 12 weeks; no objective response was noted. The median progression-free survival (PFS) durations in patients with PAM pathway alterations with and without confounding markers (KRAS, EGFR, AKT2) were 1.4 months and 2.8 months, respectively. Two patients with breast cancer (M2698/trastuzumab, n = 1; M2698/tamoxifen, n = 1) had partial response; their PFS durations were 31 months and 2.7 months, respectively.

Conclusions:

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.

News (Medical) associated with Rupitasertib

29 Jul 2024

·www.businesswire.com

Evexta Bio Appoints Robert Doebele as CMO Consultant

PARIS--( BUSINESS WIRE )--Evexta Bio SA, a clinical-stage biotechnology company focused on developing first-in-class therapies in oncology, announces the appointment of Robert Doebele as CMO consultant. Dr. Doebele's extensive academic background includes a MD and PhD in Immunology from the University of Pennsylvania School of Medicine, residency and fellowship training in Medical Oncology and Internal Medicine at the University of Chicago Pritzker School of Medicine, and a Bachelor of Arts in Molecular Biology from Princeton University. Throughout his career, Dr. Doebele has made significant contributions to cancer research, focusing on molecular diagnostics, cancer biology, and the development of biomarkers. His previous roles include Associate Clinical Professor at the University of Colorado Anschutz Medical Campus, where he also directed the Thoracic Oncology Research Initiative. Before joining Evexta Bio, Robert was co-founder, Chief Scientific Officer and Chief Medical Officer of Rain Oncology. As CMO consultant, Robert will support the Company’s clinical development strategy, provide expert advice for protocols, processes and rupitasertib clinical plans and participate in scientific advisory committees. Scott Filosi, CEO of Evexta Bio said: “ I am delighted to welcome Robert as CMO consultant. We are confident that Robert’s expertise will greatly enhance our ongoing efforts in advancing clinical research and improving patient outcomes.” About Evexta Bio ( https://www.evextabio.com ) Evexta Bio is a biopharmaceutical company exploring the new frontiers of oncology in search of daring novel therapeutic approaches with the potential to save lives. Now, in the clinic, the company is currently developing two proprietary therapeutic assets with novel mechanisms of action across several indications: Rupitasertib, an optimized S6K inhibitor with efficient AKT1/AKT3 control of compensatory AKT feed-back loop. The oral anti-tumor agent is expected to enter phase 2 clinical trial in ESR1 mt ER+ HER2- advanced breast cancer. EVX020, a sole-in-class KIF20A kinesin inhibitor having shown potent nonclinical efficacy in hematological and solid tumor models. Two strategies are under assessment, development of EVX020 as a prodrug and as a payload for antibody-drug conjugate (ADC). Founded by Truffle Capital, supported by Merck KGaA (Darmstadt, Germany) as shareholder, Evexta Bio has forged alliances with leaders in academia and industry, including CNRS, Paoli-Calmettes Institute (Marseille, France) and Merck KGaA. The company is supported by seasoned management team, board of directors and medical advisory board.

Executive ChangeADCPhase 2

22 Apr 2024

·www.biospace.com

Evexta Bio Reports Progress towards Clinical Development of Rupitasertib in Advanced Breast Cancer

Evexta Bio Reports Progress towards Clinical Development of Rupitasertib in Advanced Breast Cancer Feedback from FDA following Type B meeting enables Evexta Bio to move forward in clinical development of rupitasertib in advanced breast cancer (ABC) Phase 2 clinical trial on track to start in Q4 2024 New preclinical efficacy data strengthen rationale to develop rupitasertib, in combination with elacestrant, in ESR1mt ER+ HER2- ABC Evexta Bio to present at 10th LSX World Congress taking place in London, April 29-30, 2024 Paris, France, April 22, 2024 - Evexta Bio SA, a clinical-stage biotechnology company focused on developing first-in-class therapies in oncology, today provided an update on the clinical development of its lead asset, rupitasertib, a selective oral inhibitor of S6K and AKT1/AKT3. 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+1 HER2-2 advanced breast cancer with detectable mutation/s of the estrogen receptor 1 gene (ESR1mt). Rupitasertib is a selective oral inhibitor of S6K and AKT1/AKT3 designed to efficiently block the PI3K/AKT/mTOR (PAM) pathway while controlling the compensatory AKT feedback loop. 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 pro with preliminary signs of efficacy. Recent 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. Scott Filosi, CEO of Evexta Bio,said: "The feedback we have received from the FDA on the clinical development plan for rupitasertib, along with the new preclinical efficacy data generated in estrogen-resistant breast cancer models, is enabling us to move forward with strong confidence to initiate our Phase 2 study. Advanced breast cancer patients with ESR1 mutations who progressed on or after a CDK4/6 inhibitor have limited treatment options, and our goal is to provide them with an effective and well-tolerated therapy choice.” Dominique Bridon, CSO of Evexta Bio,added: “Patients with ER+ HER2- breast cancer often develop resistance to first-line treatment with the acquisition of ESR1 mutations, and the prognosis for these patients is poor. In addition, S6K has been shown to be closely associated with the emergence of cancer resistance, particularly in breast cancer, through ER modulation. Rupitasertib, which inhibits S6K while controlling the AKT compensatory feedback loop, could be a major advance to better treat these patients who are in need of alternative therapies.” Upcoming meeting Evexta Bio will present at the LSX World Congress in London, April 29-30, 2024. ***** About Evexta Bio ( ) EvextaBio is a clinical-stage biopharmaceutical company exploring the new frontiers of oncology in search of daring novel therapeutic approaches with the potential to save lives. The company is currently developing two proprietary therapeutic assets with novel mechanisms of action across several indications: Rupitasertib, an optimized S6K inhibitor with efficient AKT1/AKT3 control of the compensatory AKT feedback loop. The oral anti-tumor agent is expected to enter a Phase 2 clinical trial in ESR1mt ER+ HER2- advanced breast cancer later in 2024. EVX020, a sole-in-class KIF20A kinesin inhibitor that has shown potent preclinical efficacy in hematological and solid tumor models. Two strategies are under assessment - development of EVX020 as a prodrug and as an antibody-drug conjugate (ADC) payload. Founded by Truffle Capital and supported by Merck KGaA (Darmstadt, Germany) as a shareholder, Evexta Bio has forged alliances with leaders in academia and industry, including CNRS, Paoli-Calmettes Institute (Marseille, France) and Merck KGaA. The company is supported by a seasoned management team, board of directors and medical advisory board. Contact ATCG PARTNERS Marie Puvieux +33 (0)6 10 54 36 72 presse@atcg-partners.com 1 Estrogen Receptor-positive. 2 Human Epidermal growth factor Receptor 2 negative. Attachment PR in English

Phase 1Phase 2

04 Jan 2024

·www.globenewswire.com

Evexta Bio Announces the Appointment of Paul Gineste, PharmD, as Chief Development Officer

Evexta Bio Announces the Appointment of Paul Gineste, PharmD, as Chief Development Officer Paul Gineste brings 25 years of experience in clinical development and strategy with leading international pharmaceutical and biotech companies.Recently, Paul served as Vice President, Clinical Operations at Abivax, where he led the development of drug candidates from discovery through global Phase 3 programs. Paris, France, January 4, 2024 - Evexta Bio SA, a clinical-stage biotechnology company focused on developing first-in-class therapies in oncology, announces the appointment of Paul Gineste as Chief Development Officer (CDO), effective January 1, 2024. Paul is an experienced senior executive with a track record of successful achievements in the Pharma and Biotech Industry. He has worked with leading international pharmaceutical and biotech companies, including as International Clinical Trials Manager at Boehringer Ingelheim, Head of Clinical Research and Development at Altana Pharma, Executive Vice President, Clinical Development at Theravectys, a lentiviral vector spin-off from the Institut Pasteur, and most recently for 9 years as Vice President, Clinical Operations at Abivax, where he led drug candidates from discovery through global Phase 3 programs. Scott Filosi, CEO of Evexta Bio, said: "I am delighted to welcome Paul as the new Chief Development Officer of Evexta Bio. With his extensive track record in the pharmaceutical and biotech industries, Paul is the best suited to lead our clinical development and strategy as our lead candidate, rupitasertib, is expected to enter a phase 2/3 clinical trial in refractory ER+ HER2 metastatic breast cancer.” Paul Gineste, PharmD, CDO of Evexta Bio, added: “I am genuinely pleased to join Evexta Bio and its experienced management team to advance its development strategy and in particular its clinical programs. Evexta Bio has two proprietary therapeutic assets with original mechanisms of action that may address unmet medical needs in multiple cancer indications. I look forward to leading and accelerating their clinical development.” ***** Upcoming opportunity to meet our team: EVEXTA BIO will be in San Francisco, CA, during the JP Morgan's 42nd Annual Healthcare Conference, January 8-11, 2024. Contact us today to arrange a meeting with our executives in San Francisco: Scott Filosi, Chief Executive Officer, and Dominique Bridon, Chief Scientific Officer. About Evexta Bio (https://www.evextabio.com) Evexta Bio, formerly Diaccurate, is a biopharmaceutical company revolutionizing cancer treatment with potential first-in-class therapies with unique mechanisms of action for combating tumor resistance . Now in the clinic, the French biotech is currently developing two proprietary therapeutic assets across several indications: Rupitasertib, formerly DIACC3010, a first-in-class S6K inhibitor addressing tumor resistance while blocking the compensatory AKT feedback loop. The oral anti-tumor agent is expected to enter phase 2/3 clinical trial in refractory ER+ HER2- metastatic breast cancer. EVX-020, formerly DIACC2020, an antibody-drug conjugate program using a first-in-class KIF20A kinesin inhibitor as payload in hematological and solid tumors. Founded by Truffle Capital, Evexta Bio has forged alliances with leaders in academia and industry, including CNRS, Paoli-Calmettes Institute (Marseille, France) and Merck KGaA (Darmstadt, Germany). The company is supported by seasoned management team, board of directors and medical advisory board. Contacts ATCG PARTNERSMarie Puvieux+33 (0)6 10 54 36 72presse@atcg-partners.com Attachment PR in English

Executive Change

100 Deals associated with Rupitasertib

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
ER-positive/HER2-negative Breast Cancer	Phase 1	FR	Diaccurate SAStartup	22 Jul 2022
ER-positive/HER2-negative Breast Cancer	Phase 1	-	Merck KGaA	22 Jul 2022
Stomach Cancer	Phase 1	FR	Diaccurate SAStartup	22 Jul 2022
Stomach Cancer	Phase 1	-	Merck KGaA	22 Jul 2022
Solid tumor	Phase 1	US	EMD Serono, Inc.	13 Dec 2013
Glioblastoma Multiforme	Preclinical	FR	Diaccurate SAStartup	17 Nov 2023
HER2 Positive Breast Cancer	Preclinical	FR	Diaccurate SAStartup	17 Nov 2023

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01971515 (AACR2023)	Phase 1	ER-positive/HER2-negative Breast Cancer	101	DIACC3010	xbhxwmieok(xbrzgyqrjh) = annwbbtoll rsmezoeaxe (btncqmnqxm )	-	04 Apr 2023
NCT01971515 (Pubmed \| J Hematol Oncol)	Phase 1	Advanced cancer	101	M2698	sfhslagpql(bwbcxmdnxw) = no objective response was noted irbktzwhcs (acdczhcfsj )	-	18 Aug 2021
NCT01971515 (Pubmed \| J Hematol Oncol)	Phase 1	Advanced cancer	101	M2698/tamoxifen		-	18 Aug 2021

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