HRS-4642

HRS-4642 is an inhibitor of K-Ras^G12D (IC₅₀ = 2.329 nM for total RAS activity in K-Ras^G12D-expressing AsPC-1 cells).¹ It selectively binds to K-Ras^G12D over K-Ras^G12C and wild-type K-Ras (K_ds = 0.083, 1.76, and 1.38 nM, respectively). HRS-4642 also selectively inhibits the interactions between GDP-loaded K-Ras^G12D and son of sevenless homolog 1 (SOS1) and GTP-loaded K-Ras^G12D and C-RAF (IC₅₀s = 0.72 and 5.9 nM, respectively) over wild-type GDP- or GTP-loaded K-Ras with SOS1 or C-RAF (IC₅₀s = 14.98 and 171.8 nM, respectively). Moreover, it selectively inhibits the proliferation of K-Ras^G12D-expressing cancer cells over other K-Ras mutant- or wild-type K-Ras-expressing cancer cells (IC₅₀s = 0.55-66.58 and 248.5->10,000 nM, respectively). HRS-4642 (7.5 and 15 mg/kg) decreases tumor volume in multiple mouse xenograft models. It synergizes with carfilzomib (Item No. 17554) to decrease tumor volume and increase intratumoral immune cell infiltration in a KP-1 leukemia mouse xenograft model.

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1. Zhou, C., Li, C., Luo, L., et al. Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer. Cancer Cell 42(7), 1286-1300 (2024).