Delving into the Latest Updates on L-778123 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Mechanism

Ftase inhibitors(Protein farnesyltransferase inhibitors), GGTase 1 inhibitors(Geranylgeranyl transferase type I inhibitors)

Therapeutic Areas

NeoplasmsHemic and Lymphatic Diseases

Active Indication

Acute Myeloid Leukemia

Inactive Indication

Head and Neck NeoplasmsLymphomaRefractory Malignant Solid Neoplasm+ [1]

Originator Organization

Merck & Co., Inc.

Active Organization

Hannover Medical School

Inactive Organization

Merck Sharp & Dohme Corp.

National Cancer Institute

Merck & Co., Inc.

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure

Molecular FormulaC22H20ClN5O

InChIKeyJNUGFGAVPBYSHF-UHFFFAOYSA-N

CAS Registry183499-57-2

View All Structures (2)

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells.
PURPOSE: Phase I trial to study the effectiveness of combining paclitaxel and L-778,123 in treating patients who have recurrent or refractory solid tumors or lymphomas.

Start Date01 Dec 1998

Sponsor / Collaborator

Memorial Sloan Kettering Cancer Center

[+1]

NCT00003430 / CompletedPhase 1IIT

A Pharmacokinetic Study Evaluating the Safety, Tolerability and Maximally Tolerated Dose of 7-Day Continuous Infusions of L-778,123 in Patients With Recurrent of Refractory Solid Malignancies

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.
PURPOSE: Phase I trial to study the effectiveness of L-778,123 in treating patients with recurrent or refractory solid tumors.

Start Date01 Apr 1998

Sponsor / Collaborator

Memorial Sloan Kettering Cancer Center

[+1]

100 Clinical Results associated with L-778123

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100 Translational Medicine associated with L-778123

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100 Patents (Medical) associated with L-778123

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27

Literatures (Medical) associated with L-778123

01 Jan 2022·Nature NanotechnologyQ1 · MATERIALS SCIENCE

Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells

Q1 · MATERIALS SCIENCE

Article

Author: Dash, Chinmayee ; Sengupta, Shiladitya ; Saha, Tanmoy ; Mondal, Jayanta ; Kurmi, Kiran ; Majumder, Pradip K ; Bardia, Aditya ; Jang, Hae Lin ; Jayabalan, Ruparoshni ; Khiste, Sachin ; Kulkarni, Arpita

Cancer progresses by evading the immune system. Elucidating diverse immune evasion strategies is a critical step in the search for next-generation immunotherapies for cancer. Here we report that cancer cells can hijack the mitochondria from immune cells via physical nanotubes. Mitochondria are essential for metabolism and activation of immune cells. By using field-emission scanning electron microscopy, fluorophore-tagged mitochondrial transfer tracing and metabolic quantification, we demonstrate that the nanotube-mediated transfer of mitochondria from immune cells to cancer cells metabolically empowers the cancer cells and depletes the immune cells. Inhibiting the nanotube assembly machinery significantly reduced mitochondrial transfer and prevented the depletion of immune cells. Combining a farnesyltransferase and geranylgeranyltransferase 1 inhibitor, namely, L-778123, which partially inhibited nanotube formation and mitochondrial transfer, with a programmed cell death protein 1 immune checkpoint inhibitor improved the antitumour outcomes in an aggressive immunocompetent breast cancer model. Nanotube-mediated mitochondrial hijacking can emerge as a novel target for developing next-generation immunotherapy agents for cancer.

01 Jan 2017·European Journal of Medicinal ChemistryQ1 · MEDICINE

K-Ras and its inhibitors towards personalized cancer treatment: Pharmacological and structural perspectives

Q1 · MEDICINE

Review

Author: Mahapatra, Debarshi Kar ; Asati, Vivek ; Bharti, Sanjay Kumar

The discovery of genetic, genomic and clinical biomarkers have revolutionized the treatment option in the form of personalized medicine which allows to accurately predict a person's susceptibility/progression of disease, the patient's response to therapy, and maximize the therapeutic outcome in terms of low/no toxicity for a particular patient. Recently, the U.S. Food and Drug Administration has realized the contribution of pharmacogenomics in better healthcare and advocated the consideration of pharmacogenomic principles in making safer and more effective drug. Many anticancer drugs show reduced or no response in cancer patients with tumor specific gene mutations such as B-Raf and K-Ras. The high incidence of K-Ras mutation has been reported in pancreatic, colon, and lung carcinomas. The identification of K-Ras as a clinical biomarker and potential therapeutic target has attracted the scientific community to develop effective and precise anticancer drug. Inhibitors which block farnesylation of Ras have been developed or under clinical trial studies. Tipifarnib, approved by USFDA for the treatment of elderly acute leukemia is a Ras pathway inhibitor. Some peptidomimetics and bi-substrate inhibitors like FTI 276, FTI 277, B956, B1086, L731, L735, L739, L750, BMS-214662, L778123, and L778123 are under clinical trials. Recently mutant K-Ras has been considered as potential biomarker and target for precise cancer therapy. This review focuses primarily on the Ras/Raf/MEK/ERK signaling pathway including K-Ras mutation as therapeutic target, inhibitors and their structure activity relationships (SARs) for the design and development of anticancer agents.

01 Jan 2013·Advanced pharmaceutical bulletin

Comparison of Cytotoxic Activity of L778123 as a Farnesyltranferase Inhibitor and Doxorubicin against A549 and HT-29 Cell Lines.

Article

Author: Ghasemi, Saeed ; Davaran, Soodabeh ; Asgari, Davoud ; Sharifi, Simin ; Abdollahi, Ali ; Mojarrad, Javid Shahbazi

PURPOSEFarnesyltransferase (FTase) is a zinc-dependent enzyme that adds a farnesyl group to the Ras proteins. L778, 123 is a potent peptidomimetic imidazole-containing FTase inhibitor.METHODSL778123 was synthesized according to known methods and evaluated alone and in combination with doxorubicin against A549 (adenocarcinomic human alveolar basal epithelial cells) and HT29 (human colonic adenocarcinoma) cell lines by MTT assay.RESULTSL778123 showed weak cytotoxic activity with IC50 of 100 and 125 for A549 and HT-29 cell lines, respectively. The combination of doxorubicin and L778123 can decrease IC50 of doxorubicin in both cell lines significantly.CONCLUSIONIt can be concluded that L778, 123 can be a good agent for combination therapy.

100 Deals associated with L-778123

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB07227

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Preclinical	DE	Hannover Medical School	16 Nov 2008
Lymphoma	Discovery	US	National Cancer Institute	01 Dec 1998
Head and Neck Neoplasms	Discovery	US	National Cancer Institute	01 Apr 1998
Refractory Malignant Solid Neoplasm	Discovery	US	National Cancer Institute	01 Apr 1998

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASCO2004	Phase 1	Locally Advanced Pancreatic Adenocarcinoma	8	L-778,123	nzinfgfsot(vqhwhxoamv) = reversibly inhibited during L-778 treatment acakpncszu (ryjudimzol ) View more	-	15 Jul 2004