Where is the next step for targeted protein degradation?

Today, Kymera held its first R&D Day

Targeted protein degradation facilitates proteasomal degradation of target proteins by binding them to E3 ubiquitin ligases

IRAK4 protein degraders with potential to treat multiple autoimmune diseases

The company's IRAK4-targeted protein degrader has entered Phase 1 clinical trials

Previously published interim results from a single dose escalation (SAD) clinical trial showed that a single dose of KT-474 reduced IRAK4 levels in a dose-dependent manner in healthy volunteers, and the highest three doses tested were able to reduce peripheral blood mononuclear cells.

▲ A single dose of KT-474 can reduce IRAK4 levels by more than 95% (Image source: Kymera official website)

On the R&D day, the company announced clinical trial data of multiple dose escalation (MAD) of KT-474

▲ Once a day, KT-474 can maintain the lasting and almost complete degradation of IRAK4 (Image source: Kymera official website)

KT-474 can not only significantly reduce IRAK4 levels in plasma, but also reduce IRAK4 levels in skin to near undetectable levels, laying the foundation for the treatment of skin-related inflammatory diseases

▲ KT-474 significantly reduces IRAK4 levels in the skin (Image source: Kymera official website)

The company expects to initiate clinical trials in patients with atopic dermatitis and hidradenitis suppurativa in the first quarter of next year, with preliminary data expected by the middle of next year

Protein-degrading anticancer therapy that simultaneously degrades multiple targets

At the R&D day, the company also introduced an innovative protein degradation therapy called IRAKIMiD

▲IRAKIMiD mechanism of action (Image source: Kymera's official website)

In animal experiments, IRAKIMiD, named KT-413, as a single drug, showed significant anticancer activity, including the complete disappearance of MYD88-mutated tumors in some animals

Image source: Kymera's official website

Kymera plans to launch a Phase 1 clinical trial in patients with relapsed/refractory B-cell lymphoma to test its safety and preliminary efficacy

Protein degraders targeting STAT3

STAT3 is a transcription factor that can be activated by different cytokine and growth factor receptors, possibly also by mutations in oncogenic fusion proteins and STAT3 itself

▲STAT3 has multiple roles in tumor survival and growth (Image source: Kymera's official website)

Kymera's STAT3-targeting protein degrader KT-333 has resulted in complete and durable tumor regression in multiple preclinical tumor models

▲KT-333, a protein degrader targeting STAT3, resulted in complete and durable tumor regression in preclinical tumor models (Image source: Kymera’s official website)

And the company's preclinical studies have shown that STAT3-targeted degraders can change the characteristics of the tumor microenvironment and make tumors more sensitive to anti-PD-1 antibodies

KT-333 has been approved by the FDA for clinical trials, and a Phase 1 clinical trial in patients with relapsed/refractory B-cell lymphoma is expected to begin next year

In addition to playing an important role in cancer, activation of STAT3 also plays an important role in a variety of chronic inflammatory and fibrotic diseases

▲The role of STAT3 in the process of inflammation (Image source: Kymera's official website)

Kymera's STAT3 protein degraders significantly alleviate disease symptoms in animal models of systemic sclerosis, arthritis and central nervous system inflammation, showing their potential in the treatment of inflammatory diseases

Image source: Kymera's official website

Protein degraders that restore p53 function

TP53 is a well-known tumor suppressor gene.
In many cancers, mutations in the TP53 gene lead to the loss or abnormality of p53 function and induce cancer
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However, Kymera points out that p53 proteins are not mutated in nearly 50% of tumors, and that overexpression and amplification of an E3 ubiquitin ligase called MDM2 enhances the degradation of p53 proteins, leading to their inactivation
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Therefore, the targeted degradation of MDM2 may restore the activity of p53 and become a new method for the treatment of various cancers
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▲MDM2 is an E3 ligase that regulates p53 levels (Image source: Kymera official website)

KT-253, a protein degrader targeting MDM2 developed by the company, has shown better activity than MDM2 small molecule inhibitors in preclinical experiments, can stabilize the level of p53, and lead to the death of cancer cells
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Usually the use of MDM2 small molecule inhibitors will cause cells to generate more MDM2 protein through a feedback pathway, resulting in the failure of small molecule inhibitors
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However, KT-253 can overcome the influence of this feedback pathway due to the targeted degradation of MDM2 protein
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In animal models, single-dose KT-253 treatment resulted in durable tumor regression
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Image source: Kymera official website

The company plans to file an IND application in 2022, and the protein degrader has the potential to treat a variety of blood cancers and solid tumors
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Unlock a new generation of protein targets with the discovery of innovative E3 ligases

Kymera is also discovering innovative E3 ligases through its unique Targeted Protein Degradation technology platform, providing additional tools for protein degraders
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One factor limiting the use of protein degraders is that the target protein is expressed not only in diseased tissue, but also in healthy tissue, the company noted
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Targeted protein degraders, while capable of specifically degrading target proteins, can also produce side effects in healthy tissues
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E3 ligases expressed in specific tissues can limit the degradation of target proteins to specific tissues, thereby reducing potential side effects and unlocking a series of new targets
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▲Using innovative E3 ligase to unlock a new generation of targets (Image source: Kymera official website)

Kymera has discovered an E3 ligase that is expressed almost exclusively in one cell type
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Image source: Kymera official website

The company also discovered an E3 ligase that is widely expressed in cancer cells but barely expressed in one type of blood cell
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The degrader developed based on this ligase can degrade the target protein in cancer cells without affecting the expression of the target protein in blood cells, thereby improving the therapeutic index of the drug
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The company will also rationally design molecular glue therapy by cooperating with external R&D institutions to target historically "undruggable" targets
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