Table 2.

Update of EZH2 inhibitors

Compound	Details
3-Deazaneplanocin A	First EZH2 inhibitor that indirectly inhibits EZH2 via S-adenosyl-l-homocysteine increase and exerts direct repression of S-adenosyl-l-methionine-dependent histone methyltransferase activity [141]
GSK126 (GSK2816126)	A highly selective and potent inhibitor of EZH2 [142] In a phase 1 clinical trial of GSK126 conducted in patients of advanced hematologic and solid tumors, escalating doses of GSK126 (50–3000 mg, twice weekly as an intravenous solution for 28 days (3 weeks on/1 week off) were administered to 41 participants (21 solid tumors, 20 lymphoma). The outcome of the study did not demonstrate sufficient evidence of clinical activity [142]
EPZ005687	EZH2 inhibitor that possesses high affinity as well as selectivity for EZH2, however is endowed with unfavourable pharmacokinetic properties. [143]
EI1	A highly selective SAM-competitive inhibitor of EZH2 Inhibits the growth of DLBCL cells carrying Y641 mutations. [144]
GSK343	SAM-competitive inhibitors of EZH2. [145]
	The drug can suppress the levels of histone H3K27me3 and cause inhibition of EZH2 activity in breast and prostate cancer cells [145]
	The use of GSK 343 in in vivo studies might be hindered by the evidenced high clearance in rat PK studies [145]
	In a preclinical study, the antitumor effects of GSK343 on glioma cells were evaluated in vitro and in vivo. The results of the study highlighted the potential of GSK343 to reduce the proliferation, attenuate cell motility and reverse epithelial-mesenchymal transition in U87 and LN229 glioma cells. It was also observed that GSK343 suppressed the stemness of cell lines and patient derived glioma stem cells. Moreover, Histone H3K27 methylation was inhibited by GSK343 inhibited histone H3K27 methylation. Cumulatively, the results portended that GSK343 could be emerge as a potent weapon against the glioma. [146]
Tazemetostat (E7438/EPZ6438)	An orally administered, first-in-class small molecule EZH2 inhibitor [147–152]. The discovery of tazemetostat involved extensive structural engineering attempts on a bicyclic ring bearing EZH2 inhibitor (initial hit compound). As a result of the attempts centred on identifying structural prerequisites for amplifying the EZH2 inhibition, it was found that disconnecting the five-membered ring of the bicyclic core increased the potency and rendered an additional site that could be exploited for enhancing the polarity of the adducts, thereby imparting ideal physicochemical properties to the compounds. Overall, an amide tethered dimethyl substituted pyridone ring on a THP decorated aniline was found to be the key structural feature for exerting EZH2 inhibition and the installation of the benzyl morpholine ring was deduced to be instrumental in improving the physicochemical properties of the constructs. [147]
	Tazemetostat is endowed with improved potency and favourable pharmacokinetic properties in comparison to EPZ005687. [148]
	Accelerated approval was granted by US FDA to tazemetostat on 23rd January for patients with metastatic or locally advanced epithelioid sarcoma [149]
	A phase 2 clinical study of tazemetostat in patients with R/R B-cell NHL is ongoing. The interim assessment indicates that tazemetostat is endowed with preliminary clinical activity in pts with R/R DLBCL and FL. The drug was particularly found to be beneficial in subjects with tumours bearing activating EZH2 mutations. Moreover, the drug was found be safe. The results (interim efficacy results attained from 149 patients) are as follows:
	1. The ORR (CR + PR)—40% in pts with DLBCL with EZH2 mutations (N = 10),
	2. ORR—18% in pts with DLBCL with wild type (wt) EZH2 (N = 85),
	3. ORR—63% in FL pts with EZH2 mutations (N = 8) 28% in FL pts with wt EZH2 (N = 46). [25] (NCT03456726)
	In another phase 2 study, tazemetostat as single agent was evaluated in adult patients with R/R MM with BAP1 inactivation. In the study, 800 mg (po BID) of tazemetostat was administered. The results of the study are as follows:
	1.N = 74 patients, 5 pts had dose reductions due to AEs. The frequently observed AEs were Fatigue (32%), decreased appetite (28%), dyspnea (28%), and nausea (27%)
	2.Disease control was achieved in 31 pts (51%) at 12 weeks
	3.Sustained disease control was attained in 15 pts (25%) at 24 weeks, 5 of whom are ongoing 4.Overall, tazemetostat exhibited safety, efficacy as well as tolerability in patients with MM. (NCT02860286) [151]
	A Phase 1 study of tazemetostat in R/R B-cell NHL in patients with advanced solid tumours was conducted. In the study, tazemetostat was administered to 64 patients (21 with B-cell non-Hodgkin lymphoma, and 43 with advanced solid tumours). The RP2D was identified as 800 mg twice daily. Durable ORs were achieved in 8 patients out of 21 patients with B-cell NHL, while only two patients out of 43 patients with solid tumours displayed durable objective responses. Overall, the drug was found to be safe and clinically active in patients with refractory B-cell NHL and advanced solid tumours. [152] (NCT01897571)
	Tazemetostat is undergoing the below mentioned studies:
	R/R FL (Tazemetostat in combination with Lenalidomide Plus Rituximab, Phase 3, NCT04224493, status—not yet recruiting)
	Advanced Epithelioid Sarcoma (Tazemetostat in Combination with Doxorubicin, Phase 3, NCT04204941)
	R/R B-cell Non-Hodgkin's Lymphoma (Tazemetostat, Phase 2, NCT03456726, status—active, not recruiting)
	Recurrent or Persistent Endometrioid or Clear Cell Carcinoma of the Ovary, and Recurrent or Persistent Endometrioid Endometrial Adenocarcinoma (Tazemetostat, Phase 2, NCT03348631, status—suspended)
	Tumors Harboring Alterations in EZH2 or Members of the SWI/SNF Complex (Tazemetostat, Phase 2, NCT03213665, status—recruiting)
	INI1-Negative Tumors or R/R Synovial Sarcoma (Tazemetostat, Phase 2, NCT02601950, status—recruiting)
	Newly Diagnosed Diffuse Large B Cell Lymphoma (DLBCL) (Tazemetostat, Phase 1/2, NCT02889523, status—suspended)
	Advanced Solid Tumors or with B-cell Lymphoma (Tazemetostat in combination with prednisolone, phase1/2, NCT04179864, status –active, not recruiting)
	B-cell Lymphoma or Advanced Solid Tumors (Tazemetostat, Phase 1, NCT03028103, status—active, not recruiting)
	Advanced Malignancies (Tazemetostat, Phase 1, NCT04241835, status—recruiting)
	R/R B-cell Non-Hodgkin's Lymphoma (Tazemetostat, Phase 1, NCT03009344, status—active, not recruiting,)
	Tazemetostat Rollover Study (TRuST) (Tazemetostat, Phase 1, NCT02875548, status—recruiting)
	R/R INI1-Negative Tumors or Synovial Sarcoma (Tazemetostat, phase 1, NCT02601937, status—recruiting)
EPZ011989	A selective and orally bioavailable EZH2 inhibitor
	Exerts significant tumor growth inhibition in mouse xenograft model of human B cell lymphoma [153]
CPI-169	An indole based EZH2 inhibitor
	Demonstrated substantial antiproliferative activity and pharmacodynamics (PD) target engagement in a mouse xenograft model of a KARPAS-422 lymphoma
	Suffers from the issue of limited oral bioavailability [154]
CPI-1205	Optimized from the structural engineering attempts on CPI-169, CP1-1205 is also an indole based small molecule inhibitors of EZH2 [155]
	In a phase 1 study of CPI-1205 in patients with B-Cell lymphomas, CPI-1205 was administered orally twice daily (BID, in 28-day cycles) in 4 dose cohorts. The results of the study are mentioned below:
	n = 32 pts, drug related AEs were mostly grade 2 and lower, treatment-related AEs in ≥ 5% pts of any grade were nausea, diarrhea, anemia and fatigue, TRAEs ≥ grade 3 were observed in 7 patients, DLTs were not observed, CR was observed in 1 patient and SD was observed in 5 pts. CPI-1205 was found to be endowed with short half-life. Overall, the drug was found to be well tolerated with manageable toxicities. Antitumor activity was observed along with target engagement that was evaluated by assessing the H3K27me3 reduction by IHC in skin and lymphoma tissue. [156]
	CPI-1205 is presently undergoing the below mentioned studies
	mCRPC (CPI-1205 + enzalutamide or abiraterone/prednisone, Phase IB/II NCT03480646 (ProSTAR), status—active, not recruiting)
	Advanced solid tumor (phase 1/2 clinical trial, NCT03525795)
CPI-0209	Second-generation EZH2 inhibitor endowed with higher anticancer potency in comparison to first-generation EZH2 inhibitors as per the results of preclinical studies conducted in multiple cancer types
	The drug is anticipated to achieve comprehensive target coverage via extended on-target residence time [155]
	The drug is undergoing phase 1 clinical trials in patients with advanced solid tumors (CPI-02029-monotherapy and combination therapy, Phase 1/2, NCT04104776, status—recruiting)
SHR2554/SHR3680 Structure undisclosed	An orally available EZH2 inhibitor
	SHR2554 is undergoing the below mentioned clinical studies
	mCRPC (SHR2554 in combination with SHR3680 (Anti androgen, Phase 1/2, NCT03741712)
	Advanced or metastatic solid tumors and R/R B-cell lymphomas (SHR2554 in combination with Anti-PD-L1/TGFβ Antibody SHR1701, Phase1/2, NCT04407741, status—not yet recruiting)
	Phase 1 clinical investigation in patients with Refractory mature lymphoid neoplasms. (status—recruiting, NCT03603951)
ZLD1039	A highly selective, and orally bioavailable inhibitor of EZH2
	Exerts inhibition of breast tumor growth and metastasis in mice [157]
PF-06821497	A small molecule potent and selective inhibitor of EZH2
	It is active against both wild-type (wt) as well as mutant EZH2 [158]
	PF-06821497 is currently under evaluation in a phase 1 clinical trial in patients with R/R SCLC, CRPC, FL and DLBCL (NCT03460977, status—recruiting)
UNC1999	Oral SAM competitive inhibitor of wild-type (wt) and Y641 mutant EZH2 as well as EZH1 [159]
	Preclinical investigations have revealed that it effectively inhibits the growth of MLL rearranged leukemia in mice [159]
(R)-OR-S1 and (R)-OR-S2	OR-S1 and OR-S2 are S-adenosylmethionine (SAM)-competitive and highly selective
	EZH1/2 dual inhibitors
	Exhibit greater antitumor efficacy than selective EZH2 selective inhibitor against
	KARPAS-422 cells harboring a GOF mutation in EZH2 [160]
DS-3201b	A potent inhibitor of EZH1 and EZH2
	In preclinical studies, DS-320Ib has demonstrated antitumor activity against various hematological malignancies
	In a dose escalation phase 1 study in patients with R/R Non Hodgkin Lymphomas, the efficacy of DS-3201b (administered orally once daily (QD) over 28-days (1 cycle) continuously until disease progression) was evaluated. Overall, the results of the study demonstrated that DS-3201b is endowed with clinical activity and exhibited promise to be an orally available, therapeutic option for B-cell and T-cell lymphomas. Specifically, 1 CR, 7 PR and 5 SD of 15 patients (ORR = 53%) was observed. For T-cell lymphoma, ORR was 80% (1 CR and 3 PR out of 5 patients). (NCT02732275) [161, 162]
MAK683	An inhibitor of EED protein and allosteric inhibitor of PRC2
	EED-EZH2 protein–protein interaction (PPI) disruption leads to loss of H3K27me3-stimulated PRC2 activity and prevents H3K27 trimethylation, which ultimately leads to decreased tumor cell proliferation in EZH2-mutated and PRC2-dependent cancer cells. [163, 164]
	MAK683 is undergoing the below mentioned clinical study:
	DLBCL, nasopharyngeal carcinoma, gastric cancer, ovarian cancer, prostate cancer, and sarcoma (Phase 1/2 clinical trial, NCT02900651 status—recruiting) [163, 164]