HRX-0233 is a small molecule inhibitor targeting MAP2K4. In vivo, HRX-0233 effectively reduces tumors in H358 KRASG12C mutant non-small cell lung cancer (NSCLC) without significant toxicity. This compound also prevents feedback activation of receptor tyrosine kinases (RTKs) when used as a monotherapy with the KRAS inhibitor Sotorasib, leading to more sustained and comprehensive inhibition of the MAPK signaling pathway. HRX-0233 holds potential for research in AR-negative prostate cancer, lung cancer, and colon cancer.