**4.2 Small molecule inhibitors of hDOT1L**

*Translational Research in Cancer*

Lysine methyltransferases EZH2 EPZ6438

hDOT1L EPZ5676

Protein Arginine Methyltransferases PRMT5 GSK3326595(formerly EPZ015938)

(Pinometostat)

**Small molecule inhibitors**

(Tazemostat)

**Stage of development**

Phase 1 clinical

trial

trial

stage

stage

stage

trial

stage

trial

trial

stage

stage

LLY-283 Preclinical Ovarian, lung,

application

Phase 1 clinical

Phase 1 clinical

clinical trial

GSK2816126 Phase 1 clinical

CP1-1205 Phase 1b/2

EI1 Preclinical

EPZ011989 Preclinical

UNC 1999 Preclinical

EPZ 004777 Preclinical

SGC0946 Preclinical

JNJ-64619178 Phase 1 clinical

EPZ015666 Preclinical

PR5-LL-CM01 Preclinical

*List of representative small molecule inhibitors for EZH2, hDOT1L, and PRMT5.*

**Cancer treatment Reference**

[ClinicalTrials. gov] Identifier: NCT03010982

[132]

[130, 131]

[134]

[136, 137]

[138] [ClinicalTrials. gov] Identifier: NCT03724084

[139]

[140]

[ClinicalTrials. gov] Identifier: NCT02783300

[Clinical Trial identifier: NCT03573310]

[141]

[114]

[142]

FDA approved Epithelioid sarcoma [32]

and

Various lymphomas

advanced solid tumors

Lymphoma and advanced solid tumors

B-cell lymphoma, advanced solid tumors metastatic castration-resistant prostate cancer (mCRPC)

B-cell lymphoma with Y641 mutation

Diffused B-cell lymphoma with Y641N mutation and MLL rearranged

leukemia

Acute myeloid leukemia (AML)/ acute lymphoblastic leukemia (ALL)

MLL rearranged leukemia

MLL rearranged leukemia

Solid tumor and non-Hodgkin's lymphoma

Mantle cell Lymphoma

Colon and Pancreatic cancer

cancers

breast, gastric, skin, and hematological

Lymphoma [135]

**Epigenetic enzyme**

**12**

**Table 1.**

There are over 20 hDOT1L small molecule inhibitors and can be categorized into four groups based on their mode of action: (i) SAH(S-adenosyl-L-homocysteine) mimicking compounds; (ii) benzimidazole or (iii) urea group-containing compounds; and (iv) carbamate-containing compounds [143]. The activity of human homolog of yeast DOT1L or hDOT1L is mostly dysregulated in a subset of acute myeloid leukemia that has MLL gene translocation. This results in an onco-MLL protein which aberrantly recruits hDOT1L to the promoter of MLL target genes. Together with other transcription factors, hDOT1L drives the overexpression of HoxA9 and HoxA7 which leads to leukemia [141]. Hence, the need for inhibitors of hDOT1L. The first potent inhibitor of this HMT was EPZ004777 (**Table 1**), but it failed to progress through clinical development due to poor pharmacokinetics [139]. Another small molecule inhibitor, EPZ5676 (pinometostat) (**Table 1**) with Ki of less than 0.08nM, was shown to have improved pharmacokinetics and has now completed phase 1 clinical trial [138].
