PROTACs: A Promising Therapeutic Approach for Hematologic Malignancies

Sumit Sharma¹ , Harinee Yerra^1,2 and Deeksha Nayak^1,2
1. Nutralytics Edtech LLP, Pune, India
2. Department of Nutrition and Dietetics, SSCANS, Symbiosis International University, Pune, India
Correspondence to: Sumit Sharma, drsumits@outlook.com

DOI: https://doi.org/10.70389/PJI.100005

Additional information

• Ethical approval: N/a
• Consent: N/a
• Funding: No industry funding
• Conflicts of interest: N/a
• Author contribution: Sumit Sharma, Harinee Yerra and Deeksha Nayak – Conceptualization, Writing – original draft, review and editing.
• Guarantor: Sumit Sharma
• Provenance and peer-review:
  Unsolicited and externally peer-reviewed
• Data availability statement: N/a

Keywords: protacs, Haematological malignancies, Targeted protein degradation, Ubiquitin-proteasome system, Drug resistance.

Peer Review
Received: 12 February 2025
Revised: 6 March 2025
Accepted: 8 March 2025
Published: 21 March 2025

Introduction

Cancer is a highly prevalent disease, affecting one in five people globally, with over 20 million new cases and 9.7 million deaths reported in 2022.¹ Proteolysis-targeting chimera (PROTAC) is an innovative approach to treating diseases by directing cancer-causing proteins to E3 ligases for ubiquitination and subsequent degradation.² PROTACs outperform traditional inhibitors with better efficacy, selectivity, and resistance management, emerging as a breakthrough in cancer drug discovery with several advancing to clinical trials.³ PROTACs revolutionize drug development by degrading proteins with superior efficacy, targeting “undruggable” proteins, and enabling precise, reversible control for diverse diseases.⁴ Advancements like PROTAC-antibody and PROTAC-aptamer conjugates improve precision and reduce toxicity, enhancing the safety and effectiveness of PROTAC therapies.⁵ PROTACs enhance cancer therapy by targeting undruggable oncoproteins, improving specificity, reducing resistance, and minimizing side effects, especially in chromosomal instability-related cancers.⁶

Hematologic malignancies target bone marrow and hinder the bone marrow’s ability to produce blood cells. Consequently, this causes the uncontrolled production of abnormal cells and further compromises essential processes like blood coagulation and immune defense. The three main types are as follows: (1) leukemia, which causes an overproduction of faulty white blood cells; (2) lymphoma, which disrupts lymphocytes and weakens the immune system; and (3) myeloma, which impairs the production of infection-fighting antibodies.⁷ The development of these targeted medicines is needed because chemotherapy is not successful in treating hematologic malignancies. Rituximab, the first anti-CD20 monoclonal antibody (MoAb), was approved by the FDA in 1997, initiating the “rituximab era.” MoAbs are immunoglobulins that specifically target molecular markers on neoplastic cells to suppress cancer growth. The early MoAbs were mouse-derived and caused immune reactions in humans. Advances in genetic engineering produced chimeric and humanized MoAbs, with the latter containing up to 90% human sequences. Fully human MoAbs now only have human sequences. These antibodies induce apoptosis, block growth factor receptors, or modulate receptor-ligand interactions. MoAbs can be combined with radioisotopes, toxins, or other agents to enhance their therapeutic effects.⁸ This review offers a thorough overview of the most recent developments in creating PROTACs as treatment approaches for various hematologic malignancies.

Mechanism of Action of PROTAC

A new strategy for targeted protein breakdown is part of PROTAC’s mode of action. High dosages are necessary for traditional small molecule inhibitors to optimize drug receptor occupancy, which may result in unwanted side effects and off-target consequences. In contrast, PROTACs initiate target protein degradation, offering a catalytic mechanism requiring lower doses for effective protein degradation.⁹ This allows PROTACs to be administered at lower doses and longer intervals with reduced toxicity, as their action is not limited by equilibrium occupancy. The lower doses also decrease the likelihood of off-target effects, making PROTACs potentially safer and more efficient than traditional inhibitors.¹⁰ Figure 1 shows the mechanism of action of PROTACs. The molecules known as PROTACs attach ligands to the protein of interest (POI) and E3 ubiquitin ligase, with the ligands (a) binding to POI and (b) binding to E3 ubiquitin ligase, respectively. A linker is used to connect this. This binds ubiquitin to POI, indicating that the 26S proteasome is breaking down the POI.

Figure 2 shows the ubiquitin-proteasome system (UPS). It is a process that helps in breaking down unwanted proteins (degradation process). The process initiates with a target protein getting attached to a small molecule called “ubiquitin” (Ub). This includes three enzymes—E1, E2, and E3—where E1 activates Ub and passes it to the E2 enzyme, which then works with E3 and tags Ub to the protein that needs to be degraded. This process is repeated multiple times, and Ub gets attached to the target protein, resulting in the polyubiquitination of the substrate. The proteins that are tagged are then directed toward the 26S proteasome, which degrades the targeted protein molecules into smaller pieces. The cells can recycle this when needed. This is how the pathway gets rid of unwanted proteins.

Overview of Agents in Development

Figure 3 shows the various agents that are in development for the management of hematologic disorders.

NX-2127

A crucial effector of B-cell receptor (BCR) signaling is Bruton’s tyrosine kinase (BTK), a TEC family of kinases member. Many hematologic malignancies have chronic activation of BTK-mediated BCR signaling, making it a desirable treatment target. NZ-2127 is a BTK degrader that also has immunomodulatory properties. Using molecular glue connections with the cereblon E3 ubiquitin ligase complex, NX-2127 purposefully induces the degradation of transcription factors IKZF1 and IKZF3. NX-2127 breaks down BTKC481S and other well-known BTK resistance mutants. NX-2127 is bioavailable, exhibits in vivo degradation across species, and demonstrates efficacy in preclinical oncology models.¹¹ NX-2127 is a first-in-class medication with a unique dual action against BTK and IKZF3. It was studied in phase 1a for patients with small lymphocytic lymphoma and chronic lymphocytic leukemia (CLL). In addition to receiving six or more therapies, the patient group had other unfavorable prognostic characteristics, including resistance to BCL-2 noncovalent and covalent BTK inhibitors. The drug showed a 50% best overall response rate at 6 months, with no significant safety concerns. These results demonstrate that NX-2127 has excellent potential as a novel therapeutic approach and thus warranted progression to a phase 1b trial with expanded patient enrollment and dosing at 100 mg.^12,13 Figure 4 demonstrates the mechanism of action of NX-2127 in detail.

SIAIS178

SIAIS178 is a potent and selective BCR-ABL degrader based on PROTAC technology with an IC50 of 24 nM. SIASIS78 recruits Von Hippel-Lindau (VHL) E3 ubiquitin ligase, which degrades the BCR-ABL protein. There is anticancer action in SIAIS178.¹⁴ Only a particular combination of E3 ligase (CRBN), linker (6-2-2-26), and targeted ligand (Dasa) is effective for BCR-ABL-targeting PROTACs. The functional linker, 6-2-2-6, consists of three hydrophilic PEG segments flanked by hydrophobic moieties. PEG-based linkers are frequently used in PROTACs due to their excellent solubility, biocompatibility, stability, and safety in humans.¹³ Leukemogenesis in chronic myeloid leukemia (CML) is driven by the fusion protein BCR-ABL, and resistance to and prolonged usage of TKIs presents difficulties.

Dasatinib and the VHL E3 ubiquitin ligase ligand were combined to create the novel PROTAC chemical SIAIS178, which efficiently breaks down BCR-ABL, stops the proliferation of leukemic cells, and causes tumor regression in vivo. SIAIS178 also targets resistance-conferring mutations, highlighting its potential for treating BCR-ABL+ leukemia.¹⁵ N-end rule–based PROTACs are practical tools for targeting BCR-ABL, with adjustable degradation capacity, high potency, and sustained tumor growth inhibition. Short PEG-based linkers, such as Arg-PEG1-Dasa, demonstrated superior efficacy and lower resistance than traditional TKIs. Despite some limitations, these PROTACs show strong potential for optimizing cancer therapies, especially against drug-resistant mutations.¹⁶

ARV-771

ARV-825 and ARV-771 are examples of BET-PROTACs that efficiently break down BET proteins, causing more apoptosis and disruptions in MCL cells than conventional BET inhibitors. These PROTACs, especially ARV-771, show superior preclinical activity, enhanced tumor growth inhibition and survival benefits in MCL models, and synergized when combined with ibrutinib or other therapeutic agents.15 ARV-771, a PROTAC compound, is studied for its potential in treating cancer. ARV-771-tolerant RPMI-8226 cells showed substantially increased TECF mRNA expression, but c-Myc levels stayed low. In these cells, the β-catenin signaling pathway was triggered, and ARV-771-induced apoptosis was enhanced when β-catenin was knocked off. Higher IC50 values were obtained by creating drug-resistant RPMI-8226 cells (AR1, AR2, and AR3) whose resistance did not return even after 6 months off the medication. These resistant cells also showed reduced sensitivity to various other drugs and exhibited significant upregulation of ABCB1, a gene linked to drug resistance. Combining ABCB1 inhibitors or knocking out ABCB1 restored sensitivity to ARV-771 and increased apoptosis.

Gene screening identified 39 genes potentially involved in ABCB1 regulation, and further analysis highlighted C1orf112, CCDC167, and CRIP2 as significant markers for myeloma prognosis and potential targets for further research.¹⁷ K-256 selectively binds to BRD2, BRD3, BRD4, and BRDT, with the lowest binding affinity for BRD4, a key regulator of MYC transcription. Su-DHL4 and SU-DHL6 cell lines efficiently destroyed BRD4 at lower doses than dBET6 and ARV-771. With GI50 values of 12.8 nM and 7.50 nM, respectively, K-256 showed greater anticancer effectiveness and caused cell death at lower dosages than previous BET inhibitors.

According to immunoblotting, K-256 inhibited MYC expression more efficiently than current inhibitors. Both cell lines and MYC/BCL2 patient-derived xenograft models demonstrated synergistic effects when K-256 and venetoclax were combined, preventing cell proliferation and triggering apoptosis. Additionally, K-256 outperformed OTX-015 and ARV-771 in terms of therapeutic impact in vivo.¹⁸ ARV-771 has demonstrated encouraging synergistic benefits in combination therapies with other medications, including ibrutinib (a BTK inhibitor) and Venetoclax (a BCL2 inhibitor), indicating promise for augmenting the effectiveness of current treatments. This makes ARV-771 an attractive candidate for further clinical investigation. It has also shown better pharmacological properties than other BET inhibitors and degraders, such as ARV-825, highlighting its potential as a superior therapeutic option.¹⁹

Cereblon (CRBN)

Cereblon (CRBN) has recently been identified as a target for immunomodulatory drugs (IMiDs), thalidomide, lenalidomide, and pomalidomide, and its downregulation has been linked to resistance to IMiDs in multiple myeloma (MM).²⁰ Since thalidomide binds to CRBN, a substrate receptor in the CRL4CRBN E3 ubiquitin ligase complex, Japanese researchers discovered in 2010 that CRBN is the primary protein that causes thalidomide’s teratogenicity. In order to treat hematologic malignancies such as MM, non-Hodgkin lymphoma, and myelodysplastic syndromes, thalidomide analogs (ImiDs) require CRBM. IMiDs function as molecular glues, causing CRL4CRBM to ubiquitinate and degrade disease-relevant proteins selectively. Additionally, the development of PROTACs, which bind both E3 ligases like CRL4CRBN and target proteins, has further advanced the therapeutic strategy of targeted protein degradation (TPD).²¹ Studies show that IMiDs like lenalidomide induce CRBN-dependent degradation of proteins like IKZF1, IKZF3, and CK1α, advancing understanding of their mechanism in MM and MDS with del(5q).

While bortezomib paradoxically inhibits proteasomal degradation of these proteins, it might still allow effective destruction due to incomplete inhibition. Further research into CRBN’s downstream substrates and factors will help develop therapies and biomarkers for IMiD resistance and improved treatments for MM.²² Protein homeostatic modulators (PHMs) from Bio TheryX are tiny compounds using the CRBN ubiquitin ligase to degrade disease-relevant proteins. They have great promise for treating solid tumors and hematologic malignancies. These PHMs demonstrate potent cytotoxicity in acute myeloid leukemia (AML) and lymphoma cell lines, with selective activity and a wide safety window. In vivo studies show significant tumor reduction, and the compounds’ oral bioavailability makes them promising clinical candidates.²³

Thalidomide, lenalidomide, and pomalidomide bind to CRBN, a crucial protein in the CRL4CRBM E3 ligase complex, successfully curing hematologic malignancies. Through CRBN, these medications mediate the production of cytokines in T-cells and antiproliferative actions in myeloma cells. Research indicates that CRBN is essential for the medication action and that resistance to pomalidomide is associated with a reduction in CRBM expression. CRBM has been identified as a crucial therapeutic target for these immunomodulatory medications.²⁴ After thalidomide-based treatment, complete remission (CR) is associated with increased CRBN expression in CLL cells. However, it does not directly correlate with prognosis or thalidomide’s effects in CLL, suggesting that CRBN levels in the CLL microenvironment and immune cells may be more significant in determining treatment outcomes.²⁰

VHL

In VHL illness, the underlying genetic abnormality is a germline heterozygous mutation in the VHL tumor suppressor gene. When the remaining wildtype allele stops functioning, cancer develops. VHL patients are prone to developing renal cell carcinoma of the clear cell type (ccRCC) and hemangioblastoma (HB).²⁵ By encouraging the breakdown of hypoxia-inducible factor (HIF), a process interfered with in VHL deficiency, the VHL tumor suppressor protein (pVHL) controls oxygen sensing, stabilizing HIF and promoting carcinogenesis. Targeting HIF or its downstream genes, like VEGF, may offer therapeutic potential for VHL-related tumors, though emerging genotype-phenotype correlations suggest pVHL may also have functions beyond HIF regulation.²⁵ VHL mutations, often linked to sporadic ccRCC and HB, may drive extramedullary erythropoiesis in liver lesions of HOXB7-Vhl mice, suggesting a systemic etiology of HB. These mice exhibit elevated EPO levels, thrombocytopenia, and altered megakaryocyte-erythrocyte progenitor differentiation. The model highlights the potential involvement of HIF-regulated genes like CXCR4 and defects in the bone marrow environment in VHL deficiency’s hematologic effects.²⁶

In a clinical trial of belzutifan for VHL-associated kidney tumors, 61 patients took the drug once a day for 18 months. The results showed that 49% of participants had a partial response, with tumors shrinking significantly over time, including those in the pancreas, brain/spine, and eyes. Even those without a partial response experienced the most tumor reduction. Belzutifan’s side effects were mild, including fatigue, headaches, dizziness, nausea, and anemia, which were common due to the drug’s effect on blood cell production. Despite the anemia, the drug was well-tolerated and could be easily combined with other treatments.²⁷

Challenges and Opportunities in PROTAC

Key Challenges

PROTACs, which rely on E3 ligases for protein degradation, vary in activity between healthy tissues and tumors.²⁸ Several studies show that the E3 ligand, which is crucial for the development of drugs, has limitations like drug toxicity or potential risk of cells adapting resistance to the treatment, which alters the E3 ligase enzyme activity, leading to a hindrance in its effectiveness.²⁹ Several clinical trials have shown that the doses of PROTACs like ARV-110 (420 mg) are higher than traditional drugs like enzalutamide (160 mg). This indicates that the observations of the lab experiments and human behavior may vary based on the drug dosage.²⁸ Studies also show that initial treatments work effectively for the patients, but rapid cell progression leads to drug resistance in cancer patients.³⁰

Leukemia and Drug Resistance

More than 95% of the patients with CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia are linked with the BCR-ABL Fusion Gene, which is a result of the chromosomal translocation (an abnormality where a chromosome breaks and a part of this broken chromosome gets attached to a different chromosome). This gene generates BCR-ABL fusion protein, a key causative agent that disrupts the normal cell signaling process and prevents the programmed cell death (apoptosis) process, leading to more rapid leukemia progression in the patients.³¹

Several therapeutic approaches have been developed for treating AML, a type of blood cancer seen in patients. GSPT1 is one such target protein that is beneficial for treating AML. This helps stop the unwanted protein production in the cells by working with several other factors like eRF1. GSPT1 also helps remove faulty genes like mRNA, which produces faulty proteins. So, a novel drug, CC-885, was developed to break down the target protein in AML as it showed anti-cancerous effects on AML patients. However, there were several challenges during the production of CC-885, which caused some potential side effects. It was a potential risk because it targeted unintentional proteins like CK1α, HBS1L, IKZF1 (Ikaros), IKZF3 (Aiolos), and GSPT1. Furthermore, the degradation of the GSPT1 mechanism was incompletely understood, which was considered a key challenge in developing therapeutic drugs for treating AML patients.³²

Advancing TPD

PROTACs are novel drugs developed to degrade the targeted proteins in the body. They work efficiently by targeting and degrading specific proteins through the UPS.33 This is controlled by the enzymes, E3 ligases, which identify each protein for the degradation. The PROTAC approach works efficiently by modifying E3 ligases where researchers use targeted protein fragments to divert UPS to target proteins that would usually not be degraded.³⁴ This novel strategy helps PROTACs work effectively even at low dosages, which cannot be achieved without traditional drugs. As PROTAC is a novel strategy, it has gained scrutiny from several drug-producing companies, biotechnological industries, and pharmaceutical industries (Arvinas, Novartis, Bayer, and Vertex). Presently, several studies show the efficacy of this novel approach in treating several kinds of cancers, including lymphoma, by targeting (BCL6) B-cell lymphoma.³²

Recently, a new drug called SD-36, explicitly targeting and destroying the STAT3 protein, has been developed to treat certain cancers. This novel drug combines the CRBN ligand lenalidomide with SI-109, a STAT3 inhibitor that rapidly and effectively breaks the STAT3 protein in leukemia and lymphoma. In vivo studies also showed that SD-36 resulted in complete regression of tumors in mouse models, which lasted for around 2 weeks after the treatment was terminated.²⁹ A protein component called Enhancer of Zeste of homolog 2 (EZH2) controls gene expression by modifying histone activity. Elevated levels of EZH2 are usually seen in many types of cancer, including sarcoma. Current treatments that are approved clinically include EZH2 inhibitors like tazemetostat, which block the activity of EZH2 in certain types of cancers, like epithelioid sarcoma and follicular lymphoma.²⁹

Overcoming Barriers to Undruggable Targets

According to the studies, only about 20–25% of the known target proteins are currently used for drug production and disease treatments that include kinases and GPCRs, which are much easier to target. However, several other proteins have crucial functions in the body and in diseases that are not well understood, and these cannot be effectively targeted with the existing drugs. So, researchers are concentrating more on developing innovative approaches like PROTAC, which can target undruggable proteins and investigate their therapeutic applications in treating diseases like cancer.³¹

Recent advances show that researchers have added a light-sensitive component to certain drugs like pomalidomide, which gets activated by light, minimizing the side effects. Another advancement is the dTAG system, which involves the fusion of proteins that link the POI to a unique tag to induce the degradation of undruggable target proteins. LYTAC technology is another breakthrough in overcoming the barrier. This works efficiently by degrading the extracellular and membrane-related proteins. In this method, a small molecule gets attached to a glycopeptide ligand, which guides the protein to the lysosome, leading to lysosomal degradation. Researchers also developed a new approach that uses the cell’s natural way of cleaning up through a process called “autophagy” to break down unwanted proteins. This technology includes autophagy-targeting chimeras, autophagosome-tethering compounds, and chemical genetic degeneration systems like HaloPROTAC.²⁹

Clinical Efficacy of PROTACs

BTK) is a crucial target protein in treating B-cell-related cancers. Several recent clinical trials have shown promising results when a new drug called BTK PROTAC degrader was used to break down the BTK protein in cancer patients. The overall response of one of the BTK degraders—BGB-16673—in the phase 1 clinical trial was 67% in 12 out of 18 patients. This included a mantle cell lymphoma patient who showed CR response, but most of these patients (88.5%) observed side effects of the treatment. Another novel orally administered drug is NX-5948, which was well-tolerated without any dosage toxicity in the patients. One out of three CLL patients exhibited partial improvement after 2.8 months of treatment with this novel drug. Another drug is NX-2127, which is a dual-functioning degrader. This drug targets BTK and immune-related proteins like IKZF1 and IKZF3. After 9.5 months of follow-up to the treatment, some patients with non-Hodgkin’s lymphoma showed lasting responses.^35,36

Future Considerations

Novel approaches like PROTAC, a targeted protein degrader, have given hope for cancer treatment in cases challenging to treat using existing therapies like tyrosine kinase inhibitors.³⁷ Several opportunities are available to improve TPD. One central area of focus is targeting the “undruggable” proteins like transcriptional factors, which lack the active site for traditional therapeutic drugs to get attached. This poses a potential opportunity to transform weak and inactive molecules to bind and work effectively in degrading the undruggable proteins. The hydrophobic tag-based degraders should be explored more in the future as they have the potential to be used as a practical treatment approach, which can be taken as an oral medication to treat several kinds of cancers. Over the years, TPD has made remarkable achievements in treating patients, but several challenges need to be addressed. More advanced therapeutic approaches are likely to be designed and clinically tested, which can be effectively used in treating cancer patients.³⁸

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Cite this article as:
Sharma S, Yerra H and Nayak D. PROTACs: A Promising Therapeutic Approach for Hematological Malignancies. Premier Journal of Immunology 2025;2:100005

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