Table 1.
Summary of in vivo studies using compounds that inhibit BRD4 hyperphosphorylation
| Compound | Target | In vivo studies and references |
| Flavopiridol | CDK1/2/4/6/7/9 | Flavopiridol significantly inhibits tumor growth in one of the two NMC xenograft lines (47). |
| Flavopiridol prolongs survival in murine transplanted models of MLL-ENL–transformed cells (48). | ||
| Flavopiridol has potent antitumor activity in human leukemia and lymphoma xenografts (49). | ||
| Flavopiridol has modest to significant activities in relapsed CLL in clinical trials (50, 51). | ||
| PHA-767491 | CDC7/CDK9 | PHA-767491 has antitumor activity in rodent models of human leukemia, human colon carcinoma, and DMBA-induced mammary carcinomas (52). |
| C646 | p300 | C646 suppresses in vivo growth of transplanted AE9a leukemia blasts in mice (53). |
| C646 suppresses tumor growth in a lung cancer xenograft and a leukemia xenograft (54). | ||
| (+)-JQ1 | BRD4/BRD4-NUT | JQ1 promotes tumor regression and prolongs survival in murine models of NMC (19). Therapeutic effects for JQ1 were observed in mouse models of hematological malignancies, such as acute myeloid leukemia, multiple myeloma, and lymphoma, and in some solid tumors, such as neuroblastoma, breast cancer, and prostate cancer (10–14, 55, 56). |
| OTX015/MK-8628 (A JQ1 analog) | BRD4/BRD4-NUT | Among four patients with advanced-stage NMC treated with OTX015/MK-8628, two patients responded rapidly with tumor regression and symptomatic relief, and a third had meaningful disease stabilization with a minor metabolic response (57). |
| HMBA | Releases CDK9 from its inactive complex; induces HEXIM1; targets p300 and BRD4 (43) | HMBA induces a sharp decrease in tumorigenicity in a murine model of human colon cancer (58). |
| HMBA slightly promotes tumor regression and prolongs survival in murine models of human oral squamous cell carcinoma (59). | ||
| A phase II clinical trial was conducted using HMBA to treat patients with MDS or AML. Of the 41 patients in the trial, HMBA induced a complete remission in three patients and a partial remission in six patients (60). |
AE9a, AML1-ETO 9a fusion gene; AML, acute myelogenous leukemia; CLL, chronic lymphocytic leukemia; DMBA, 7,12-dimethylbenz(a)anthracene; MDS, myelodysplastic syndrome; MLL-ENL, mixed-lineage leukemia (MLL) oncogenic fusion caused by the translocation between chromosomes 11 and 19 (also called eleven nighteen leukemia, ENL); NMC, NUT midline carcinoma.