Delving into the Latest Updates on Apitolisib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Apitolisib (USAN/INN)

+ [4]

Target

Class I PI3K x mTORC1 x mTORC2

Action

inhibitors

Mechanism

Class I PI3K inhibitors(PI3-kinase class I inhibitors), mTORC1 inhibitors(Mammalian target of Rapamycin (mTORC1) inhibitors), mTORC2 inhibitors(mTOR Complex 2 inhibitors)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal DiseasesUrogenital Diseases+ [2]

Active Indication-

Inactive Indication

Advanced breast cancerCastration-Resistant Prostatic CancerLocally Advanced Malignant Solid Neoplasm+ [5]

Originator Organization

Genentech, Inc.

Active Organization-

Inactive Organization

Genentech, Inc.

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC23H30N8O3S

InChIKeyYOVVNQKCSKSHKT-HNNXBMFYSA-N

CAS Registry1032754-93-0

This multicenter, international, Phase Ib/II trial consists of three stages: a Phase Ib, open-label stage in which the recommended Phase II dose was determined for ipataseritib administrated in combination with abiraterone and of apitolisib administrated in combination with abiraterone (this phase is no longer active), a Phase II, 3-arm, double-blind, randomized comparison of ipatasertib with abiraterone and prednisone/prednisolone versus placebo with abiraterone and prednisone/prednisolone and a safety single-arm, open-label cohort of ipatasertib 400 mg daily alone or in combination with prednisone/prednisolone or prednisone/prednisolone plus abiraterone.

Start Date11 Jan 2012

Sponsor / Collaborator

Genentech, Inc.

NCT01487239

/ CompletedPhase 1

A Phase I Study to Investigate the Absorption, Metabolism, and Excretion of [14C]-GDC-0980 Following Single Oral Dose Administration in Healthy Postmenopausal Female Subjects

This study will be an open-label, non-randomized, absorption, metabolism, and excretion study of [14C]-GDC-0980 administered as a 10-mg oral dose to 6 healthy postmenopausal and/or surgically sterile female subjects following at least a 10-hour fast from food (not including water).

Start Date01 Dec 2011

Sponsor / Collaborator

Genentech, Inc.

NCT01455493

/ CompletedPhase 2

A Multicenter, Single-Arm, Open-Label, Phase II Study of GDC-0980 for The Treatment of Recurrent or Persistent Endometrial Carcinoma

This is a multicenter, single-arm, open-label Phase II study to evaluate the activity of GDC-0980 in patients with recurrent or persistent endometrial cancer. The safety, tolerability, and pharmacokinetics of GDC-0980 will also be evaluated.

Start Date01 Dec 2011

Sponsor / Collaborator

Genentech, Inc.

100 Clinical Results associated with Apitolisib

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100 Translational Medicine associated with Apitolisib

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100 Patents (Medical) associated with Apitolisib

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137

Literatures (Medical) associated with Apitolisib

01 Sep 2024·European Journal of Pharmacology

Targeting the RAS upstream and downstream signaling pathway for cancer treatment

Review

Author: Hossain, Md Arafat

Cancer often involves the overactivation of RAS/RAF/MEK/ERK (MAPK) and PI3K-Akt-mTOR pathways due to mutations in genes like RAS, RAF, PTEN, and PIK3CA. Various strategies are employed to address the overactivation of these pathways, among which targeted therapy emerges as a promising approach. Directly targeting specific proteins, leads to encouraging results in cancer treatment. For instance, RTK inhibitors such as imatinib and afatinib selectively target these receptors, hindering ligand binding and reducing signaling initiation. These inhibitors have shown potent efficacy against Non-Small Cell Lung Cancer. Other inhibitors, like lonafarnib targeting Farnesyltransferase and GGTI 2418 targeting geranylgeranyl Transferase, disrupt post-translational modifications of proteins. Additionally, inhibition of proteins like SOS, SH2 domain, and Ras demonstrate promising anti-tumor activity both in vivo and in vitro. Targeting downstream components with RAF inhibitors such as vemurafenib, dabrafenib, and sorafenib, along with MEK inhibitors like trametinib and binimetinib, has shown promising outcomes in treating cancers with BRAF-V600E mutations, including myeloma, colorectal, and thyroid cancers. Furthermore, inhibitors of PI3K (e.g., apitolisib, copanlisib), AKT (e.g., ipatasertib, perifosine), and mTOR (e.g., sirolimus, temsirolimus) exhibit promising efficacy against various cancers such as Invasive Breast Cancer, Lymphoma, Neoplasms, and Hematological malignancies. This review offers an overview of small molecule inhibitors targeting specific proteins within the RAS upstream and downstream signaling pathways in cancer.

01 Sep 2024·The Journal of Clinical Pharmacology

Quantitative Assessment of Drug Efficacy and Emergence of Resistance in Patients with Metastatic Renal Cell Carcinoma Using a Longitudinal Exposure‐Tumor Growth Inhibition Model: Apitolisib (Dual PI3K/mTORC1/2 Inhibitor) Versus Everolimus (mTORC1 Inhibitor)

Article

Author: Wong, Harvey ; Wright, Matthew R. ; Moein, Anita ; Jin, Jin Y.

AbstractCancer remains a significant global health challenge, and despite remarkable advancements in therapeutic strategies, poor tolerability of drugs (causing dose reduction/interruptions) and/or the emergence of drug resistance are major obstacles to successful treatment outcomes. Metastatic renal cell carcinoma (mRCC) accounts for 2% of global cancer diagnoses and deaths. Despite the initial success of targeted therapies in mRCC, challenges remain to overcome drug resistance that limits the long‐term efficacy of these treatments. Our analysis aim was to develop a semi‐mechanistic longitudinal exposure‐tumor growth inhibition model for patients with mRCC to characterize and compare everolimus (mTORC1) and apitolisib's (dual PI3K/mTORC1/2) ability to inhibit tumor growth, and quantitate each drug's efficacy decay caused by emergence of tumor resistance over time. Model‐estimated on‐treatment tumor growth rate constant was 1.7‐fold higher for apitolisib compared to everolimus. Estimated half‐life for loss of treatment effect over time for everolimus was 16.1 weeks compared to 7.72 weeks for apitolisib, suggesting a faster rate of tumor re‐growth for apitolisib patients likely due to the emergence of resistance. Goodness‐of‐fit plots including visual predictive check indicated a good model fit and the model was able to capture individual tumor size–time profiles. Based on our knowledge, this is the first clinical report to quantitatively assess everolimus (mTORC1) and apitolisib (PI3K/mTORC1/2) efficacy decay in patients with mRCC. These results highlight the difference in overall efficacy of 2 drugs due to the quantified efficacy decay caused by emergence of resistance, and emphasize the importance of model‐informed drug development for targeted cancer therapy.

26 Jul 2024·Endocrinology

High-throughput Screening for Cushing Disease: Therapeutic Potential of Thiostrepton via Cell Cycle Regulation

Article

Author: Fujita, Haruka ; Kosugi, Daisuke ; Ueda, Yohei ; Sugawa, Taku ; Yamauchi, Ichiro ; Okamoto, Kentaro ; Fujii, Toshihito ; Hakata, Takuro ; Inagaki, Nobuya ; Taura, Daisuke

AbstractCushing disease is a life-threatening disorder caused by autonomous secretion of ACTH from pituitary neuroendocrine tumors (PitNETs). Few drugs are indicated for inoperative Cushing disease, in particular that due to aggressive PitNETs. To explore agents that regulate ACTH-secreting PitNETs, we conducted high-throughput screening (HTS) using AtT-20, a murine pituitary tumor cell line characterized by ACTH secretion. For the HTS, we constructed a live cell–based ACTH reporter assay for high-throughput evaluation of ACTH changes. This assay was based on HEK293T cells overexpressing components of the ACTH receptor and a fluorescent cAMP biosensor, with high-throughput acquisition of fluorescence images. We treated AtT-20 cells with compounds and assessed ACTH concentrations in the conditioned media using the reporter assay. Of 2480 screened bioactive compounds, over 50% inhibition of ACTH secreted from AtT-20 cells was seen with 84 compounds at 10 μM and 20 compounds at 1 μM. Among these hit compounds, we focused on thiostrepton (TS) and determined its antitumor effects in both in vitro and in vivo xenograft models of Cushing disease. Transcriptome and flow cytometry analyses revealed that TS administration induced AtT-20 cell cycle arrest at the G2/M phase, which was mediated by FOXM1-independent mechanisms including downregulation of cyclins. Simultaneous TS administration with a cyclin-dependent kinase 4/6 inhibitor that affected the cell cycle at the G0/1 phase showed cooperative antitumor effects. Thus, TS is a promising therapeutic agent for Cushing disease. Our list of hit compounds and new mechanistic insights into TS effects serve as a valuable foundation for future research.

100 Deals associated with Apitolisib

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External Link

KEGG	Wiki	ATC	Drug Bank
D10543	-	-	DB12180

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced breast cancer	Phase 2	Italy	Genentech, Inc.	01 Oct 2011
Advanced breast cancer	Phase 2	France	Genentech, Inc.	01 Oct 2011
Advanced breast cancer	Phase 2	Hong Kong	Genentech, Inc.	01 Oct 2011
Advanced breast cancer	Phase 2	United States	Genentech, Inc.	01 Oct 2011
Advanced breast cancer	Phase 2	Singapore	Genentech, Inc.	01 Oct 2011
Advanced breast cancer	Phase 2	Argentina	Genentech, Inc.	01 Oct 2011
Advanced breast cancer	Phase 2	United Kingdom	Genentech, Inc.	01 Oct 2011
Advanced breast cancer	Phase 2	Russia	Genentech, Inc.	01 Oct 2011
Advanced breast cancer	Phase 2	Spain	Genentech, Inc.	01 Oct 2011
Advanced breast cancer	Phase 2	Denmark	Genentech, Inc.	01 Oct 2011

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01455493 (MAGGIE, Pubmed \| Cancer) Manual	Phase 2	Endometrial Carcinoma PI3K Mutation	56	GDC-0980	(fpdlnsjnyt) = sclxghifiu tuvyvsxzry (gvgqyjnhqb ) View more	Positive	15 Nov 2016
NCT00854152 (Pubmed \| Clin Cancer Res) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	120	Apitolisib	(pxcjjssiot) = hyperglycemia (18%), rash (14%), liver dysfunction (12%), diarrhea (10%), pneumonitis (8%), mucosal inflammation (6%), and fatigue (4%). syblaewmbu (xilzlfopka ) View more	Positive	15 Jun 2016
NCT01442090 (Pubmed \| J Urol) Manual	Phase 2	Metastatic Renal Cell Carcinoma VHL Mutation \| HIF1 Expression	85	Apitolisib	(atgqtpidhh) = ntrikmlqsh pdgjbeaeqo (vbzegnlnpt ) View more	Negative	10 May 2016
NCT01442090 (Pubmed \| J Urol) Manual	Phase 2		85	Everolimus	(atgqtpidhh) = rlbddjvqxz pdgjbeaeqo (vbzegnlnpt ) View more	Negative	10 May 2016
NCT01442090 (ASCO2014)	Phase 2	Metastatic Renal Cell Carcinoma	85	GDC-0980 (G)	(rbgygigqic) = oewuwrjixk mmcbpjukud (nqpdokpxds ) View more	Negative	20 May 2014
NCT01442090 (ASCO2014)	Phase 2	Metastatic Renal Cell Carcinoma	85	Everolimus (E)	(rbgygigqic) = vncagoheal mmcbpjukud (nqpdokpxds ) View more	Negative	20 May 2014
NCT01455493 (ASCO2014)	Phase 2	Advanced Endometrial Carcinoma	56	GDC-0980 40 mg	(wrwozepdwj) = uepncqkeuv ndtjmigxvu (heyyadxaus ) View more	-	20 May 2014