Activation of RAS and PI3Kalpha are the most frequent oncogenic events in cancer, playing a key role in many aspects of tumor cell physiology, including growth, survival, differentiation, and migration. While treatment options have recently emerged for a subset of KRAS mutant patients and inhibitors of PI3Kalpha catalytic activity have been approved, both approaches have been limited by drug resistance and in the case of PI3Kalpha, hampered by poor tolerability (e.g., hyperglycemia). An alternative therapeutic strategy that addresses drug resistance with improved tolerability is needed. Application of the FrontierTM platform, which integrates chemoproteomics, AI, and covalent fragment-based drug discovery, enabled the discovery of FMC-242, a potent, selective, and orally bioavailable covalent inhibitor of the PI3Kalpha -RAS family interactions disrupting oncogenic RAS and RTK signaling without impacting the insulin homeostasis. FMC-242 rapidly and selectively forms a covalent bond with cysteine 242 in the RAS Binding Domain (RBD) of PI3Kalpha resulting in allosteric inhibition of PI3Kalpha -RAS complex formation. This leads to inhibition of AKT activation in tumors with mutations in KRAS or PI3Kalpha, and where receptor tyrosine kinases, e.g., HER2, are activated. FMC-242 treatment of CDX and PDX models carrying HER2 amplification and/or KRAS mutation results in potent anti-tumor activity including regressions. FMC-242 is well tolerated in vivo, and inhibition of PI3Kalpha -RAS interaction does not impact insulin signaling or blood glucose level. Combination of FMC-242 with targeted therapies including EGFR inhibitors, KRASG12C inhibitors such as FMC-376, divarasib, olomorasib, or pan-RAS/KRAS agents results in enhanced efficacy and tumor regressions in vivo. Together, these data demonstrate the potential of FMC-242, a selective covalent inhibitor of PI3Kalpha -RAS interaction, to deliver improved outcomes for patients as monotherapy and in combination with targeted therapies in the clinic.