Mechanism of Action

 

Kirsten rat sarcoma (KRAS) belongs to the family of small GTPases and is one of the most frequently mutated genes in tumors. Its biological function in promoting tumor growth has been extensively studied. The mutation of glycine to cysteine (G12C) at position 12 of the KRAS protein constitutively activates downstream signaling pathways such as RAF-MEK-ERK and drives tumor cells to proliferate continuously.


Although it was discovered nearly 40 years ago, KRAS has always been regarded as an “undruggable target” by the pharmaceutical industry due to the smooth surface of the KRAS protein and the lack of a small-molecule binding pocket. However, in 2013, Professor Kevan M. Shokat of the University of California, San Francisco discovered a new binding pocket, switch-II (S-IIP) that can be induced and brought a new dawn for the development of KRAS inhibitors.

Jacobio designed the small-molecule allosteric inhibitor Glecirasib using its own allosteric inhibitor platform. Glecirasib is a potent, irreversible KRAS G12C inhibitor. Glecirasib covalently binds to the mutated cysteine residue on site 12 of GDP-bound KRAS G12C. This locks KRAS G12C in an inactive state, blocking KRAS-dependent signal transduction. This inhibition results in favorable anti-tumor effects by reducing the growth and proliferation of tumor cells and inducing apoptosis.

Glecirasib has not only high selectivity and potency, but also has unique utility due to its unique molecular structure. The drug has demonstrated better efficacy and safety in early clinical studies compared other standard of care treatments. The drug also had an extremely low gastrointestinal toxicity profile that resulted in better overall patient compliance. Glecirasib is potentially a best-in-class drug and is expected to benefit non-small cell lung cancer and colorectal cancer patients with KRAS G12C mutations.

 

 

Indications

The KRAS G12C mutation accounts for up to 11.3% of KRAS mutations with its presence in about 5-13% of patients with non-small cell lung cancer, 3% of patients with colorectal cancer, and a lower proportion of patients with several other refractory cancers. Glecirasib can be used to treat solid tumors with KRAS G12C mutations such as non-small cell lung cancer and colorectal cancer and other solid tumors with this mutation as either monotherapy or in combination with either the SHP2 inhibitor JAB-3312 or with anti-PD-1 antibody.

Clinical trial

Monotherapy


Assets

Region

Phase

Indication

Registration Information

Glecirasib

China

IIb

Advanced Solid Tumors

ClinicalTrials: NCT05009329

CDE Number: CTR20211470

China IIb

Pancreatic Cancer

CDE Number: CTR20232444

ClinicalTrials: NCT06008288

Combination Therapy

Assets

Partners

Region

Phase

Indications

Registration Information

Glecirasib

Cetuximab

(EGFR  mAb)

China

IIa

Advanced Colorectal Cancer, etc.

ClinicalTrials: NCT05194995

CDE Number: CTR20220015

U.S.

IIa

Advanced Solid Tumors 

ClinicalTrials: NCT05002270

JAB-3312

(SHP2i)

China

IIa

Advanced Solid Tumors 

ClinicalTrials: NCT05288205

CDE Number: CTR20220587

JAB-3312+Glecirasib VS Tirelizumab+Pemetrexed+Carboplatin

China

III

NSCLC

ClinicalTrials: NCT06416410

Posters & Publications  

Glecirasib (JAB-21822, KRAS G12C inhibitor) Monotherapy and in Combination with Cetuximab in Patients with Advanced Colorectal Cancer

Jacobio Pharma presented clinical results of glecirasib at the JCA-AACR Precision Cancer Medicine International Conference

 

A Phase I/II study of first-in-human trial of Glecirasib (KRAS G12C inhibitor) in advanced solid tumors

Jacobio presented Phase I clinical data of KRAS G12C inhibitor Glecirasib at the 2022 annual meeting of American Society of Clinical Oncology (ASCO)

 

Results of KRAS G12C inhibitor Glecirasib as a single agent or in combination with SHP2 inhibitor JAB-3312

Jacobio presented the results of Glecirasib as a single agent or in combination with JAB-3312 in preclinical cancer models during the 2022 European Society of Medical Oncology ASIA (ESMO ASIA)

 

References

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