Bromodomain and Extra-Terminal Motif Inhibitors: a Review of Preclinical and Clinical Advances in Cancer Therapy

Figures & data

Figure 1.  Biology of bromodomain and extra-terminal inhibitors and their role in cancer therapy.

BET protein binds to acetylated histones and recruits, via its BRD4 domain, PTEF-b to sites of active transcription of growth-promoting genes such as MYC and NUT. In addition, the ET domain of BRD4 independently recruits transcriptional activators such as NSD3, JMJD6 and CHD4 to further increase rates of transcription. BET inhibitors block the initial binding of BET proteins to acetylated histones, and thus halts the transcriptional cascade of oncogenes.

BET: Bromodomain and extra-terminal; PTEF-b: Positive transcriptional elongation factor complex.

Table 1. Preclinical (in vitro) inhibitory activity of bromodomain and extra-terminal inhibitors with their respective clinical structures.

BET inhibitor	Ki^† (nM)	IC50^¶ (nM)	Chemical structure
JQ1	10.7 ± 1.1	77
OTX015	6.0 ± 0.3	75–650
BET-d246	<1	<10
ABBV-075	1-2.2	<100
I-BET 151	20–100	790
I-BET 762	30.3	35
CPI 203	50–90	37
PFI-1	49 × 10^3	220
RVX-208^‡	195	510–600
Dinaciclib^§	37 × 10^3	50–90

^†to BD2 of BRD4 domain unless otherwise specified.

^‡to BD2 of BRD3.

^§to BRDT.

^¶IC₅₀ variation within ranges reflect variability of tested cell lines.

BET: Bromodomain and extra-terminal.

Table 2. Clinical trials of bromodomain and extra-terminal inhibitors.

Target	BETi agent	Target population	Study Phase	Sponsor	Trial no.
BRD2/3/4, BRDT	ABBV-075	Solid tumors, AML, MM, NSCLC, breast cancer	I	Abbvie	NCT02391480
	FT-1101	AML, MDS	I	Forma Therapeutics/Celgene	NCT02543879
	GSK525762/I-BET762	Hematological malignancies (AML, MM, BCL-2/MYC-driven cohorts NMC, SCLC, NSCLC, CRC, NB, CRPC, TNBC, ER-positive breast cancer	I I/II (open)	GlaxoSmithKline GlaxoSmithKline	NCT01943851 NCT01587703
	INCB057643	Any advanced/recurrent malignancy	I/II	Incyte Corporation	NCT02711137
	ZEN003694	Metastatic CRPC Metastatic CRPC + enzalutamide	I I	Zenith Epigenetics	NCT02705469 NCT02711956
BRD2/3/4	OTX015/MK-8628	AML, DLBCL Solid tumors (NMC, TNBC, CRPC, NSCLC) GBM NMC harboring BRD4-NUT, TNBC, NSCLC harboring ALK-KRAS fusion, CRPC, PC AML, DLBCL, ALL, MM	I I Phase II (Withdrawn) I I	Merck/Mitsubishi Tanabe Merck/Mitsubishi Tanabe Merck/Mitsubishi Tanabe OncoEthix GmbH OncoEthix GmbH	NCT02698189 NCT02698176 NCT02296476 NCT02259114 NCT01713582
BRD2/4	GSK2820151/I-BET151	Solid tumors	I	GlaxoSmithKline	NCT02630251
BRD2	CC-90010	Advanced solid tumors, relapsed/refractory NHL	I	Celgene	NCT03220347
BRD4	CPI-0610	Lymphoma MM AML, ALL, CML Peripheral nerve sheath tumors II (not yet open)	I I I I	Constellation Pharmaceuticals/Roche	NCT01949883 NCT02157636 NCT02158858 NCT02986919
	PLX51107	Solid tumors, lymphoma, AML, MDS	I	Plexxicon	NCT02683395
	ABBV-744	AML and prostate cancer	I	Abbvie	NCT02391480
Undisclosed	BAY1238097	Solid tumors and lymphoma	I (Terminated)	Bayer	NCT02369029
	BI 894999	Solid tumors and NHL	I	Boehringer Ingelheim	NCT02516553
	BMS-986158	Solid tumors	I/II	Bristol-Myers Squibb	NCT02419417
	GS-5829	DLBCL, peripheral T-cell lymphoma, solid tumors ERþ breast cancer in combination with exemestane or fulvestrant Metastatic CRPC as single agent and in combination with enzalutamide	I I/II I/II	Gilead	NCT02392611 NCT02983604 NCT02607228
	INCB054329	Solid tumors, hematological malignancies	I/II	Incyte Corporation	NCT02431260
	RO6870810/TEN-010	MDS, AML	I	Hoffman-LaRoche	NCT02308761

ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; BETi: Bromodomain and extra-terminal inhibitor; CML: Chromic myeloid leukemia; CRPC: Castration-resistant prostate cancer; DLBCL: Diffuse large B-cell lymphoma; GBM: Glioblastoma multiforme; MDS: Elastodynamics syndrome; MM: Multiple myeloma; NB: Neuroblastoma; NHL: Non-Hodgkin lymphoma; NSCLC: Non-small-cell lung carcinoma; SCLC: Small-cell lung carcinoma; TNBC: Triple-negative breast cancer.

Table 3. Combination therapy using bromodomain and extra-terminal inhibitors.

Author (year)	Combination	Model used	Outcome
BET inhibitor + epigenetic inhibitor Loosveld et al. (2014) [49] Borbely et al. (2015) [64] Stratikopoulos et al. (2015) [93] Fiskus et al. (2014) [50] Bauer et al. (2018) [99]	HDAC inhibitor SAHA Mocetinostat Kinase inhibitor PI3K inhibitor + JQ1/MS417 JQ1 + FLT3-TK1 Ponatinib + JQ1/dBET1	Ex vivo screening assay Mice xenografted with human primary T-ALLs Breast cancer cells Broad range of cancer cell lines NOD/SCID mice injected with OCIAML3 or MOLM13 cells Colon (HCT116, HT29), breast (MCF-7, SKBR3) and ovarian (A2780, SKOV3) cancer cells	Reduces MYC expression Reduced breast cancer cell viability via induction of ULP17 Combined treatment-induced cell death, tumor regression and clamped PI3K signaling in various cancer cell lines Significantly attenuates the expression of c-MYC, BCL2 and CDK4/6, while synergistically inducing apoptosis of cultured and primary CD34^+ human AML blast progenitor cells Sensitizes colon, breast and ovarian cancer cells to JQ1 and dBET1; combination of these two types of inhibitors increased apoptosis and downregulated MYC
BET inhibitor + cell cycle inhibitor Tontsch-Grunt et al. (2016) [94] Bolin et al. (2016) [95]	BI 894999 and CDK9 inhibitors Alvocidib and LDC000067 Unidentified BET and CDK2 inhibitors	Mice injected with MV-4-11, THP-1 and MOLM13 cells Mice transplanted with medulloblastoma	Synergistic inhibition of tumor growth and MYC expression Synergistic effect on tumor growth inhibition and improvement of overall survival
BET inhibitor + immune check point inhibitor Hogg et al. (2017) [52]	JQ1 and PD-L1 antibodies	Mice with Myc-driven lymphoma	Synergistic response in mice with lymphoma
BET inhibitor + DNA damage repair inhibitors Muralidharan et al. (2016) [96]	RVX2135 and ATR inhibitor AZ20	λ820 and λ2749 murine Myc-induced lymphoma xenografts	Synergistic delay in tumor onset in λ820 xenografts; synergistic WBC reduction and improved survival in λ2749 xenografts
BET inhibitor + chemotherapeutic drugs Loosveld et al. (2014) [49] Bui et al. (2017) [73] Bui et al. (2017) [73] Bui et al. (2017) [73] Stuhlmiller et al. (2015) [68]	JQ1+Vincristine ABBV-075 +Venetoclax ABBV-075 +Bortezomib ABBV-075 + Azacitidine JQ1 + Lapatinib	Ex vivo screening assay Mice xenografted with human primary T-ALLs AKM1 AML xenografts AKM1 AML xenografts AKM1 AML xenografts ERRB2-positive breast cancer cell lines resistant to lapatinib	Reduces MYC expression Induced apoptosis via modulation of the intrinsic apoptotic pathway, tumor regression Synergistic effect on tumor regression with better tolerance by xenografts than BET inhibitor monotherapy Combination treatment with JQ1 and lapatinib showed stronger growth inhibitory effect of ERRB2-positive breast cancer, reduced levels of ERBB3, IGF1R, DDR1, MET and FGFR

ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; ATR: Ataxia Telangiectasia Mutated and RAD-3 related ; BET: Bromodomain and extra-terminal; FGFR: FGF receptor; HDAC: Histone deacetylase; MET: Tyrosine-protein kinase; NOD/SCID: Nodulation Factor/Severe Combined Immune Deficiency; SAHA: Suberanilohydroxamic acid; WBC: White Blood Cells.

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