JQ1

Overview

JQ1 is a potent, selective BET (bromodomain and extra-terminal) bromodomain inhibitor developed as a tool compound. It targets BRD4 (and related BRD2/BRD3), displacing them from acetylated histone marks and suppressing transcription of oncogenes including MYC. JQ1 has known pharmacokinetic limitations and is not clinically approved, but is widely used to establish preclinical proof-of-concept for BET inhibition.

Evidence in the corpus

  • JQ1 IC50 values positively correlate with ARID1A expression levels in SCLC cell lines (r = 0.368, P = 0.032, GDSC1 dataset), indicating enhanced JQ1 sensitivity upon ARID1A loss PMID:22037554.
  • JQ1 dose-dependently reduces RAD51 expression and suppresses p-CHK1 levels in SCLC cells PMID:22037554.
  • Combination of JQ1 and brd-k98645985 (targeting the ARID1A-containing BAF complex) achieves superior tumor suppression vs. either agent alone in xenograft models (p < 0.0001) PMID:22037554.
  • Bliss synergy between JQ1 and BRD-K98645985 demonstrated in vitro in SCLC cell lines PMID:22037554.
  • MYC amplification (~14% of pancreatic ductal adenocarcinoma cases, associated with poor overall survival and adenosquamous histology) nominates BET-bromodomain inhibitor JQ1 as a therapeutic candidate PMID:25855536
  • JQ1 (50 mg/kg daily orally) significantly slowed tumor growth in 2 grade-2 adenoid cystic carcinoma (ACC) primagrafts (X5M1, X9), with modest decreases in MYB and MYB-target gene expression; both grade-3 Notch-activated primagrafts failed to respond, implicating BRD4 occupancy at MYB super-enhancers as a grade-2-specific dependency PMID:26829750
  • BET inhibitor JQ1 shows preclinical benefit in KDM6A-loss bladder cancer (Ler et al. 2017, cited); KDM6A loss affects ~5% of MIBC by focal deletion plus inactivating mutations in a subset, and the BRD4-EZH2 axis is proposed as a combination-therapy target in MIBC PMID:28988769

Resistance mechanisms

  • ARID1A-high SCLC tumors show reduced sensitivity to JQ1, as high ARID1A expression positively correlates with IC50 PMID:22037554.
  • Grade-3 ACC primagrafts with activating NOTCH1 mutations or SPEN loss-of-function are insensitive to JQ1 in vivo, indicating that Notch pathway activation confers intrinsic BET-inhibitor resistance in ACC PMID:26829750

Cancer types (linked)

  • SCLC
  • ACC (adenoid cystic carcinoma) — grade-2 tumors sensitive; grade-3 Notch-activated tumors resistant PMID:26829750

Sources

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