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ARTICLE | Product Development

KRAS’s next chapter: hitting the target’s active form 

Investors rewarded Revolution for preclinical KRAS (ON) data at AACR23, as a wave of dual KRAS (ON/OFF) inhibitors at the meeting gear up for the clinic

April 25, 2023 5:48 PM UTC

Compounds inhibiting the active form of KRAS are poised to challenge the first generation of inhibitors, which lock the target in its “OFF” state. At least six companies presented preclinical data at AACR for agents capable of inhibiting active KRAS; two are already in the clinic, and the other four are slated to enter by 1Q24.

The new entrants believe that by blocking the ability of active KRAS-GTP to interact with downstream effector molecules such as RAF proteins, they’ll out-perform the two marketed drugs from Amgen Inc. (NASDAQ:AMGN) and Mirati Therapeutics Inc. (NASDAQ:MRTX) targeting the inactive, GDP-bound form of the KRAS G12C mutation, which both have response rates of about 40%, median progression-free survival (PFS) of less than seven months, and hepatotoxicity risk...

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