The Application of BH-3 Only Mimetics in Tumor Therapy

Chunzi Jiang

1,a,†

, Zheng Wang

2,b,*,†

and Yang Yang

3,c,*,†

School of Engineering and Applied Sciences, State University of New York at Stony Brook, New York, U.S.A.

The College of Liberal Arts and Sciences, Arizona State University, Tempe, U.S.A.

School of Life Sciences, University of Glasgow, Lanarkshire, Glasgow, U.K.

†

These authors contributed equally

Keywords:

BH-3 Only Protein, BH-3 Only Protein Mimetics, BCL-2 Family, Apoptosis.

Abstract:

Tumors are divided into benign and malignant, and the further development of malignant tumors becomes

cancer. In recent years, the number of deaths from cancer worldwide increasing rapidly. To better fight cancer,

targeted therapy is a more precise method. Among them, BH-3 only protein is a representative protein for

targeted therapy. BH-3 only protein is a BCL-2 family protein with only one BH domain and acts as a pro-

apoptotic protein to regulate cell apoptosis. Different BH-3 only proteins have different binding options with

anti-apoptotic proteins in the BCL-2 family. BH-3 only protein has an excellent performance in inhibiting

cancer cells, and the research of BH-3 only mimics constantly updated. This paper will introduce drug

research on tumor treatment by studying the effects of targeted BH-3only mimics and expanding drugs'

development for its related family proteins.

1 INTRODUCTION

Programmed cell death, or apoptosis, is a unique form

of suicidal cell death accompanied by cell size

reduction and chromatin concentration (Kroemer et

al. 2005). Apoptosis controls the number of cells in

an organism, eliminating harmful or virus-infected

cells. There are mainly three pathways regulating

apoptosis: mitochondria-mediated pathway, death

receptor pathway, and endoplasmic network pathway

(Kerr, Wyllie, Currie 1972). The interactions of the

BCL-2 family control the mitochondrial apoptosis

pathway (Levine, Sinha, Kroemer 2008). Structural

feature similarity is determined by sequence

homology. Hydrophobic slits are formed between the

four (BH1-BH4) domains of protein-protein

interaction, which are involved in the proapoptotic

protein BH3 domain uptake through

heterodimerization. BCL-2 anti-apoptotic proteins

include BCL-2, BCL-W, BCL-XL, MCL-1, and A1

(BCL2A1/ BCL-1), containing four BH homologs

have similar protein 3D structures (Figure 1a)

(Shamas-Din, et al. 2011).

The balance of these interactions determines the

life cycle length of the cells expressing the

corresponding protein. PUMA, BIM, tBID can bind

to all members (Ley, et al. 2005, Qian, Zhang, Zhi

2017). TBID can antagonize the pro-survival

function of BCL-2 and can directly combine with

BAX and BAK to initiate apoptosis (Merino, et al.

2009, Hutt 2015). Except for BH-3, only protein,

which can bind to any pro-survival protein, the

binding of other BH-3 only proteins are selective

(Figure 1b). BH-3 only protein will be selected based

on the above binding to respond to apoptosis signals

so that these BCL-2 anti-apoptotic proteins are

isolated from BAX and BAK (Singh, Letai, Sarosiek

2019).

As of 2018, among the 18 million cases of cancer

globally, the number of deaths is estimated to have

reached 9.6 million, and cancer has become the

world's second prominent cause of death (Copur

2019). During the research process, the excellent

therapeutic effect of targeted drug therapy emerged

as a hot research object in cancer treatment

worldwide. BH-3 mimics anti-tumor drugs are a new

type of anti-tumor drugs targeting BCL-2 family anti-

apoptotic member proteins. This article will

introduce the clinical drug course and progress of

BH-3only mimics developed by the selective binding

of different BH-3 only proteins.

Jiang, C., Wang, Z. and Yang, Y.

The Application of BH-3 Only Mimetics in Tumor Therapy.

DOI: 10.5220/0011295300003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 791-796

ISBN: 978-989-758-595-1

791

Figure 1: BCL-2 family protein structure and selective binding.

2 BH-3 ONLY MIMETICS

Cancer cells are different from normal cells in that

they have three major characteristics: infinite

proliferation, transformability, and easy metastasis.

These characteristics bring great difficulties to the

treatment of cancer. Since discovering the apoptotic

properties and three-position structure of BCL-2 anti-

apoptotic family proteins, research on its chemical

resistance and protein inhibitors has continued.

Targeted cancer treatment is the current mainstream

idea of clinical treatment of cancer to improve the

cure rate and the survival time of patients.

Overexpression of anti-apoptotic BCL-2 family

proteins can drive cancer cell proliferation or

resistance to chemotherapy drugs. The combination

of BH-3 only protein and the anti-apoptotic BCL-2

family protein leads to the release and activation of

Bak and Bax, which leads to cell apoptosis.

Therefore, BH3 mimics have great prospects in

developing drugs targeting the anti-apoptotic BCL-2

protein (Baell, Huang 2002).

2.1

Target BCL-2 Protein2.2 Target

MCL-1 Protein

2.1.1 S55746

Its selective characteristics indicate that it does not

significantly bind to MCL-1, BFL-1 (BCL2A1/A1),

and has a poor affinity for BCL-XL. S55746 can be

taken orally and is not harmful to BCL-X1-dependent

cells such as platelets. The combination of S55746

and ABT-199 is different. S55746 occupies the

S1/2/3 region and forms a hydrogen bond with the

carboxyl group of the A149 skeleton in the S2 residue

(Casara, et al. 2018), forming a highly specific

binding. ABT-199 occupies more protein surface

area, including S2/3/4/5 (Souers, et al. 2013).

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2.1.2 Phenothiazine

Tumor cells have developed a variety of strategies to

achieve proliferative advantages. Researchers are

developing chemicals to impede the interaction

between the pro-apoptotic protein, thereby

mimicking the mechanism of action between the pro-

apoptotic protein and the BH-3 domain (Degterev, et

al. 2001). Other drugs in the article, such as ABT-737

and ABT-263, have appeared and used for many

years. To increase the treatment of tumors, the

interaction between phenothiazine and biofilm is due

to the amphiphilic nature of the molecule. The

thiazide core is relatively hydrophobic (Philot, et al.

2016, Homem-de-Mello, Mennucci, Tomasi, et al.

2005). Therefore, phenothiazine drugs have a great

potential for the anti-apoptotic protein BCL-2

inhibitory effect and appear in the actual treatment

process as drugs for the treatment of tumors.

2.1.3 Gossypol /ApoG2

Gossypol is a polyphenol extracted from the

Campagnaceae plant (Flack, et al. 1993). Gossypol is

helpful in human clinical trials of stage ii cancer.

Gossypol is a well-known toxic compound. However,

Apogossypolone (ApoG2) can be obtained by

removing two aldehyde groups (Arnold, et al., 2008).

Moreover, in clinical trials, due to the existence of

two reactive aldehyde groups, which are related to

side effects of gossypol, such as vomiting and

diarrhea, the design and synthesis of ApoG2

eliminates the reactive groups, minimizing side

effects, and ApoG2 has higher stability and efficacy

than its parent compound.

Follicular lymphoma (FL) is the fifth most

diagnosed cancer (Rogers 2005). ApoG2 was found

to be used in the treatment of follicular lymphoma.

Lymphoma (FL is very effective, it inhibits cell

growth by lysing the cell lymphoma cell line (WSU-

FSCCL). The cell growth inhibition rate is 50%. In

nasopharyngeal carcinoma cells, ApoG2 completely

blocks the anti-apoptotic function of BCL-2 family

proteins (McDermott, Dutt, Watkinson 2001).

ApoG2 has three types. Researchers have shown

through research that ApoG2 may be a new BCL -2

family protein inhibitor. By targeting these proteins,

it may become a promising drug for the treatment of

nasopharyngeal carcinoma.

2.2 Target MCL-1 Protein

2.2.1 S63845

As a BH-3 mimic, S63845 can bind to MCL1 with

high affinity and specificity. S63845 can effectively

kill MCL1-dependent cancer cells, although as a

single drug, it can effectively act on multiple

myeloma, leukemia, and lymphoma cells (Kotschy, et

al. 2016). S63845 binds to MCL-1 more efficiently

and specifically. The binding affinity of S63845

synthetic MCL-1 inhibitor for MCL-1 is 20 times that

of A-1210477, and the effect of killing MCL1-

dependent H929 multiple myeloma cells is 1000

times that of A-1210477 (Merino, et al. 2017, Li, Z.,

He, and Look 2019). The combination of S63845 and

ABT-737, ABT-263, ABT-199, which have a low

binding capacity to BCL-1, can improve the

therapeutic efficacy (Merino, et al. 2017).

Experiments have shown that the combined

administration of S63845 and ABT-199 can more

effectively induce human T-lymphocytic leukemia

(T-ALL) cells (Li, Z., He, and Look 2019).

2.2.2 S64315/MIK665

S64315 is simulant S63845, and the effect is better

than S68345 (Hird and Tron 2019). Compared with

S63845, there is no clinical trial (Szlavik, et al. 2020).

Acute myeloid leukemia (AML), myelodysplastic

syndrome (MDS) (NCT03672695 and NCT

02979366), and multiple myeloma (MM)

(NCT02992483), the first phase of MDS and MM

trials just ended in March 2021.

2.2.3 VU661013

VU661013 is a derivative of indole-2-carboxylic

acid, which can reduce the expansion of AML cell

lines (Ramsey, et al. 2018). VU661013 can also make

ER+ breast cancer cells apoptosis and will not up-

regulate BCL-2 or BCL-XL in ER+ breast cancer

cells during treatment (Williams, et al. 2019), which

is better than S68345.

2.3 Target BCL-XL Protein

2.3.1 A-1155463/A-1331852

BCL-XL is an anti-apoptotic protein located in

mitochondria and one of the key factors of cell

apoptosis. Malignant pleural mesothelioma (MPM)

has been tested with a series of BH-3 mimics, and

BCL-XL is the main pro-survival protein. Malignant

pleural mesothelioma (MPM) is one of the cancers

The Application of BH-3 Only Mimetics in Tumor Therapy

793

with the lowest survival rate. This experiment

discovers that BCL-XL is a feasible breakthrough in

treating malignant pleural mesothelioma (MPM)

(Arulananda, et al. 2020). A-1331852 is a potent and

selective BCL-XL inhibitor that can be taken orally.

Using structure-based drug design to redesign the

BCL-XL inhibitor A-1155463 reported earlier is also

a further discovery of BCL-XL inhibitors. The

inhibitor is a small molecule (Wang, et al. 2020).

Research on A-1155463 found that it has a huge

effect on BCL-XL-dependent tumors, and it also

retains the cell system of BCL-2 and MCL-1. The

Epstein-Barr virus (EBV) related T cell and natural

killer (NK) cell malignancies, A-1331852-induced

apoptosis ENKTL cell line SNK6 established a

xenograft model provides evidence that A-1331852

treatment may be effective It is beneficial in vivo

(Arulananda, et al. 2020). After treatment with A-

1331852, it can continue to induce apoptosis to

achieve the therapeutic effect.

2.4 Target Multiple Proteins

2.4.1 ABT-737

ABT-737, as a kind of BH-3 only mimic, can bind to

Bcl-2, BCL-W, and BCL-XL (Shin, et al. 2015).

ABT-737 leads cancer cells to apoptotic, but it is

harmful to common cells (Oltersdorf, et al. 2005).

Although it just can be combined with the MCL-1 that

involves many apoptosis pathways, ABT-737 still has

excellent prospects in clinical. Overexpression of

MCL-1 and A1 will weaken the sensitivity of cells to

drugs. If MCL-1 is inactivated, overexpression of

BCL-2 will not reduce the cytotoxic activity of ABT-

737 for cancer cells, but overexpression of BCL-CL

will relatively reduce the efficacy of the drug. Mcl-1

is an unstable protein, and the half-life of Mcl-1

mRNA and MCL-1 protein is very short (Anderson,

et al. 2016). Seliciclib, cyclin-dependent kinase

inhibitor and protein synthesis inhibitor

cyclohexylamine (CHX), can reduce MCL-1 levels

and significantly increase the sensitivity of cells to

ABT-737 (F.van 2006). This report shows that the

combination of inactivated MCL-1 and ABT-737 is

promising for clinical treatment. It has been reported

that ABT-737 is particularly sensitive to acute

myeloid leukemia stem cells. Phenformin can

increase cell sensitivity more on this basis, and ABT-

737 combined with phenformin can be more suitable

for targeting hematological malignancies (Velez, et

al. 2016).

2.4.2 ABT-263

ABT-737 is the most successful and potential BH3

mimic compound developed by Abbott. In recent

years, this mimic has played an indispensable role in

regulating apoptosis therapy. However, ABT-737

also has restrictions. That is, it cannot be taken orally.

The full name of ABT-263 is navitoclax (Tse, et al.

2008). But it is different from ABT-737. For

chemotherapeutics that use drugs to adjust cell

apoptosis, cell apoptosis resistance caused by

inducing factors is a key hindrance to cancer control.

To study this problem, a phase I experiment was

conducted in 2007 (Gandhi, et al. 2011). These

problems reflect the need for improvement of ABT-

263. In the records of Gernot et al. in 2015, wogonin,

apigenin, chrysin, etc., can reduce the efficacy of

enhancing ABT-263 and thus reduce the dosage of

drugs (Polier, et al. 2015). In an experiment on ABT-

263 in 2020, ABT-263 affected bone changes and cell

damage to a certain degree in aged mice (Sharma, et

al. 2020). The experiment is based on the in vitro oral

administration of several groups of old mice. The use

of isolation and contrast culture of bone marrow

stromal cells from ABT-263 or carrier-treated mice

obtained experimental results.

2.4.3 ABT-199

Following ABT-737 and ABT-263, there have been

new advances in BCL-2 inhibitors. ABT-199 is a new

type of small molecule inhibitor. Although the first

two have targeted treatment characteristics, the

selectivity of ABT-199 is special. The treatment of

tumors by BH-3 mimics is achieved by adding drugs

to the metabolic mechanism. ABT-199 can resist

tumors and reduce the damage to certain cells during

treatment (Davids and Letai 2013). As mentioned

above, ABT-263, the inhibitor, can be taken orally

and cause damage to platelets. Souers and colleagues

redesigned reverse engineering in which ABT-199

selectively killed BCL-2 cells without destroying

BCL-XL cells. Proved that ABT-199 is a highly

effective and selective inhibitor. In other

developments, ABT-199 has also made new

breakthroughs (Jakubowska, et al. 2019). It will not

destroy the steady state of certain ions in the internal

environment. ABT-199 has a slight effect on the

content of ions in the solute and does not significantly

change the ion steady state in PAC. It is superior to

earlier BCL-2 inhibitors. Therefore, the side effects

of ABT-199 when used in the treatment of leukemia

are relatively low. In recent years, it has been

clinically discovered that a deacetylase inhibitor

chidamide (CS055) combined with ABT-199

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

794

treatment can ensure cell viability and enhance ABT-

199 activity (Chen, et al. 2020, Lucantoni, et al.

2018). In breast cancer treatment, selective inhibitors

of BCL-2 and BCL-Xl slow down the synthesis of

ATP and lethal cancer cells (Szlavik, et al. 2020).

However, the overexpression of the drug in certain

lymphoid

malignancies is caused by drug resistance.

Through the whole genome screening of human acute

myeloid leukemia (AML), it is known that the

mitochondrial structure causes a sensitive response to

ABT-199. In the end, Kristina et al. proved that

mitochondrial chaperone protein (CLPB) directly

interacts with the main regulator of mitochondrial

dynamics (OPA1) (Chen, et al. 2019). It is possible

that evasion of ABT-199 resistance can be achieved

by targeting mitochondria.

3 CONCLUSIONS

BH-3 protein plays an indispensable role in cell

apoptosis by selectively binding to BCL-2 family

anti-apoptotic proteins and inducing apoptosis. ABT-

737, ABT-263, and ABT-199 promote the

oligoylation of BAX and BAK and, eventually, the

apoptosis of cancer cells. They have shown efficacy

in some cancer cases and play an indispensable role

in regulating apoptosis therapy. S63845, S64315, and

VU661013 are all bH-3 mimics that inhibit BCL-1

and reduce the amplification of AML cell lines. A-

1331852 is a practical, oral selective inhibitor of

BCL-XL. ApoG2 study provides new ideas for

nasopharyngeal carcinoma, respectively. Each of

these drugs has its advantages but is not sufficient on

its own because of the complexity of cancer and

apoptotic procedures. Clinical studies have shown

that combinations of drugs that impede BCL-2 and

McL-1 proteins can improve treatment outcomes,

such as the combination of S63845 and ABT-199,

which can prolong the life of patients. This suggests

that BH-3 mimics still have a promising application

in cancer treatment.

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