GDC-2992 is a selective and orally active androgen receptor (AR) degradator that degrades AR (DC50 = 2.7 nM) and inhibits proliferation (IC50 = 9.7 nM) in VCaP cells, making it suitable for studying castration-resistant prostate cancer (CRPC).

EGFR (L858R):1.1  nM, EGFR (WT): 5.6 nM

GDC-2992 exhibits potent inhibitory activity against multiple EGFR mutations, particularly EGFR L858R and T790M/L858R, with IC₅₀ values of 1.1 nM and 1.0 nM, respectively. In the H1975 lung cancer cell line (harboring the T790M/L858R mutation), it inhibits cell proliferation with an IC₅₀ of 5.6 nM and effectively suppresses phosphorylation of downstream signaling proteins including p-EGFR, p-AKT, and p-ERK. GDC-2992 shows weak inhibition of wild-type EGFR (IC₅₀ > 100 nM), indicating strong selectivity for mutant forms[1].

In NSG mice bearing H1975 xenograft tumors, GDC-2992 administered orally once daily (QD) demonstrated dose-dependent antitumor activity, achieving near-complete tumor regression at 100 mg/kg. The compound significantly reduced p-EGFR levels in tumor tissue, confirming effective target engagement in vivo[1].