TARGETS:

KRAS G12C mutations

INDICATIONS:

KRAS G12C mutation-positive cancers with an initial focus on Non-Small Cell Lung Cancer (NSCLC) and Colorectal Cancer (CRC)

STATUS:

IND-enabling studies

MRTX849 is advancing toward an IND submission in the fourth quarter of 2018. MRTX849 is a potent, highly selective and orally available small molecule inhibitor of a form of KRAS that harbors an oncogenic substitution mutation (G12C). KRAS G12C is a well-validated driver mutation present in approximately 14% of NSCLC adenocarcinoma patients and 5% of CRC patients. Patients with KRAS mutation-positives cancers generally have a poor prognosis and resistant to standard therapies.

MRTX849 has demonstrated broad-spectrum antitumor activity across a panel of KRAS G12C-positive patient- and cell-derived in vivo tumor models, including complete tumor regression in a subset of these models. MRTX849 may be the first KRAS mutant-selective inhibitor to enter clinical trials, thus providing a long-awaited targeted therapy option for patients exhibiting a KRAS driver mutation.

Mirati owns the worldwide rights to MRTX849.

Preclinical Development

In preclinical studies, MRTX849 is highly potent in blocking KRAS-dependent signal transduction and cancer cell viability (EC50 ~10 nM). MRTX849 also demonstrated >1,000-fold selectivity for inhibition of KRAS G12C-compared with other cellular proteins. In in vivo models, MRTX849 has displayed broad-spectrum antitumor activity across a panel of KRAS G12C-positive patient- and cell-derived tumors, achieving frank tumor regression in most models including complete tumor regression in a subset of models.

MRTX849 exhibited predicted human oral bioavailability of >30% and a half-life of ~20 hours, as well as a therapeutic index of up to 10-fold in repeat-administration toxicology studies. MRTX849 appears to possess significantly improved potency and a higher degree of antitumor activity than reported previously for other KRAS mutant-selective inhibitors and is the first such molecule reported to advance to IND-track development.

Scientific Basis for Advancement of Potent KRAS Inhibitors

Historically, the oncogene KRAS has been extremely difficult to directly inhibit due to its high affinity for GTP and its lack of a defined binding pocket.   The identification of small molecule fragments that covalently modify cysteine 12 resulting from KRAS G12C mutations and discovery of a novel expandable binding pocket proximal to cysteine 12 were critical advancements in the design of drugs that directly inhibit mutated KRAS.

Mirati’s KRAS program emerged from a joint drug discovery collaboration with Array BioPharma, where over 150 co-crystal structures and creation of >2,000 novel small molecules provided critical insights toward the design of potent and selective KRAS inhibitors with drug-like properties. Optimized compounds were subsequently developed that bind this pocket and lock KRAS in its GDP-bound inactive form, preventing KRAS from exerting its aberrant oncogenic signaling and malignant transformation.  The unique biding interaction with KRAS G12C, potency, and selectivity of MRTX849 clearly distinguish this molecule from other attempts at directly targeting KRAS and it appears to be the first molecule in its class to advance to IND-track development.