A deep dive into JAKs, TKIs, and other classes

Kinases regulate nearly every aspect of cellular function – they act as molecular switches, controlling cell signaling pathways involved in growth, metabolism, immune responses, and apoptosis. Their dysregulation has been implicated in numerous diseases, particularly cancer. This is where kinase inhibitors come into play.

Kinases have become one of the most extensively targeted enzymes in drug development. While traditional chemotherapies broadly attack dividing cells, kinase inhibitors are more specific. 

They have been very successful in oncology with therapies such as imatinib (Gleevec), now established as an important treatment of chronic myeloid leukemia (CML). But their contributions go beyond oncology as they are investigated for autoimmune diseases, fibrosis, and even neurodegenerative conditions.

Given the sheer diversity of kinases and their inhibitors, this article will break down the major categories, highlight breakthrough therapies, and spotlight the exciting innovations shaping the next wave of targeted treatments.

Tyrosine kinase inhibitors (TKIs): A game changer in cancer therapy

Tyrosine kinase inhibitors (TKIs) have become increasingly important in the treatment of multiple cancers. They basically work by blocking signaling pathways that drive tumor growth in cancer. Specifically, TKIs target tyrosine kinases – enzymes that normally regulate cellular growth, survival, and differentiation but, when dysregulated, drive unchecked cell division and tumor formation.

Imatinib (Gleevec) – developed by Novartis – has to be the TKI breakthrough. It changed how chronic myeloid leukemia (CML) is treated by selectively inhibiting the BCR-ABL fusion protein – a continuously active kinase caused by a chromosomal translocation. This kinase sends constant growth signals, causing uncontrolled white blood cell proliferation. Gleevec works by blocking the ATP-binding site of BCR-ABL, preventing leukemia cell growth. 

Most TKIs work by blocking the ATP-binding site of tyrosine kinases. However, drug resistance is a major challenge with this approach. To overcome this, next-generation TKIs have been designed to target resistance mutation, bind outside the ATP site to reduce side effects, or improve blood-brain barrier penetration to treat brain metastases.

A subcategory of TKIs emerges: Bruton’s tyrosine kinase (BTK) inhibitors. They regulate immune cell signaling instead of growth factor receptors and have gained traction in B-cell malignancies as BTK is overactive in these kinds of cancers.

The first-generation BTK inhibitor, ibrutinib, was initially very effective but led to resistance mutations. New non-covalent BTK inhibitors like nemtabrutinib are now in development to bypass these resistance mechanisms. Indeed, beyond BTK inhibitors, several TKIs are currently in development.

Noteworthy TKIs currently in development

Nemtabrutinib (MK-1026)

• Developer: Merck
• Target: BTK
• Indication: Chronic lymphocytic leukemia
• Stage: Phase 3

Nemtabrutinib is a reversible (non-covalent) BTK inhibitor, developed to overcome a resistance mechanism found in patients treated with first-generation BTK inhibitors like ibrutinib, acalabrutinib, and zanubrutinib.

Traditional BTK inhibitors, such as ibrutinib, bind covalently to the BTK enzyme at the C481 cysteine residue. However, many patients eventually develop C481S mutations, leading to drug resistance.

Nemtabrutinib does not rely on covalent binding. Instead, it binds to both wild-type and mutant BTK via non-covalent interactions, maintaining efficacy where first-generation BTK inhibitors fail.

Remibrutinib

• Developer: Novartis
• Target: BTK
• Indication: Chronic spontaneous urticaria (CSU)​
• Stage: Phase 3

Remibrutinib is an oral BTK inhibitor indicated for CSU, an autoimmune skin disorder where patients develop recurring itchy hives and swelling without an identifiable trigger. Novartis shared some data from the phase 3 trial in 2024 indicating a favorable safety and efficacy profile.

IDRX-42

• Developer: IDRx (recently acquired by GSK)
• Target: KIT 
• Indication: Gastrointestinal stromal tumors (GIST)
• Stage: Phase 1/1b

IDRX-42 is a selective small molecule inhibitor targeting mutations in the KIT tyrosine kinase, which are implicated in the pathogenesis of GIST. In February 2025, GSK announced its acquisition of IDRx for a $1 billion upfront payment.

NVL-655

• Developer: Nuvalent
• Target: Anaplastic lymphoma kinase (ALK)
• Indication: ALK-positive non-small cell lung cancer (NSCLC)
• Stage: Phase 1

ALK-positive NSCLC is a major area for TKIs, and resistance is a key challenge. NVL-655 is a selective ALK inhibitor designed to address resistance mutations and improve central nervous system (CNS) penetration. Early trial results have shown a 38% response rate in patients with advanced ALK-positive NSCLC.

Cyclin-dependent kinase (CDK) inhibitors: Targeting the cell cycle in cancer

In healthy cells, DNA replication is ensured by the proper regulation of CDK activity. However, when CDK signaling is disrupted, it leads to uncontrolled cell growth. In cancer, overactive CDKs bypass normal checkpoints and tumors divide indefinitely.

This makes CDK inhibition a solid strategy in oncology, more specifically in hormone receptor-positive (HR+), and HER2-negative breast cancer. The first-generation CDK inhibitors – palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio) – all target CDK4/6.

However, CDK4/6 inhibitors have their limitations. Many tumors develop resistance by switching to alternative CDK pathways, pushing for the next-generation CDK inhibitors to target CDK2, CDK7, and CDK9, to overcome that resistance.

Indeed, CDK2 inhibitors target tumors that become resistant to CDK4/6 blockade such as breast, ovarian, and lung cancers. CDK7 inhibitors disrupt both cell cycle control and transcription, making them effective for aggressive cancers. CDK9 inhibitors suppress cancer gene transcription, starving tumors of proteins.

It is still early but some promising next-generation inhibitors are currently being investigated.

Noteworthy CDK inhibitors currently in development

PF-07104091

• Developer: Pfizer
• Target: CDK2
• Indication: Hormone receptor-positive (HR+), HER2-negative advanced/metastatic breast cancer, ovarian cancer, small cell lung cancer
• Stage: Multiple phase 1 trials

F-07104091 selectively binds to and inhibits CDK2. This inhibition results in reduced phosphorylation of the retinoblastoma protein (Rb), leading to cell cycle arrest and preventing the proliferation of cancer cells. 

Milciclib

• Developer: Tiziana Life Sciences
• Target: CDK1, CDK2, CDK4, CDK7
• Indication: Non-small lung cancer (NSCLC), thymic cancer
• Stage: Phase 2

Milciclib is a pan-CDK inhibitor that targets multiple CDKs, tropomyosin receptor kinases, and Src family kinases, which are involved in cancer cell growth and malignant progression.

JAK inhibitors: The inflammation fighters

Janus kinase enzymes are part of the JAK-STAT signaling pathway involved in the formation of blood cells and immune functions. When this pathway becomes overactive, it can lead to disorders like myeloproliferative neoplasms and autoimmune diseases. 

The first big win in this field came in 2011 with the approval of Incyte Corporation’s drug, ruxolinitinib (Jakafi) – the first JAK inhibitor to reach the market. This JAK 1 and JAK2 inhibitor was developed for myelofibrosis and polycythemia vera – disorders where the bone marrow produces too many blood cells.

Beyond blood disorders, JAK inhibitors are also investigated in autoimmune diseases. Tofacitinib (Xeljanz) is the first oral JAK inhibitor for rheumatoid arthritis. It was also later approved for psoriatic arthritis and ulcerative colitis. Another example would be upadacitinib (Rinvoq), also approved for rheumatoid arthritis with fewer side effects than tofacitinib. It’s also being explored for Crohn’s disease and atopic dermatitis.

The list of JAK inhibitors currently being tested in the clinic is long, here are a few examples.

Noteworthy JAK inhibitors currently in development

Brepocitinib

• Developer: Pfizer licensed to Priovant Therapeutics
• Target: Dual JAK1/TYK2 inhibitor
• Indication: Plaque psoriasis, lupus, ulcerative colitis
• Stage: Multiple clinical trials

Brepocitinib was originally developed by Pfizer for psoriatic arthritis (PsA), lupus, and ulcerative colitis but the company has since deprioritized the candidate. However, Brepocitinib was since out-licensed to Priovant which is conducting a phase 3 trial for dermatomyositis, a chronic inflammatory disease affecting skin and muscles. There is also an ongoing phase 2 study in non-infectious uveitis (NIU), an inflammatory eye condition that can lead to vision loss.

Povorcitinib (INCB054707)

• Developer: Incyte Corporation
• Target: JAK1 inhibitor
• Indication: Hidradenitis suppurativa & chronic prurigo
• Stage: Phase 2

Phase 2 trials’ preliminary results demonstrated that povorcitinib reduced abscess and inflammatory nodule counts in hidradenitis suppurativa patients. Hidradenitis suppurativa is a chronic, inflammatory skin disease that causes painful lumps, abscesses, and tunnels under the skin. The phase 2 clinical trial is still ongoing.

Zasocitinib (TAK-279)

• Developer: Takeda
• Target: TYK2 inhibitor
• Indication: Psoriatic arthritis, plaque psoriasis
• Stage: Phase 3

TYK2 inhibition is a new strategy in autoimmune disease, showing good efficacy with fewer JAK-related side effects like infections and blood clot risks. Takeda shared positive TAK-279 phase 2b results for plaque psoriasis and initiated phase 3 trials in 2023.

​PI3K, AKT, and mTOR inhibitors – The survival blockers

The PI3K/AKT/mTOR pathway is a regulator of cancer cell growth and survival, making it a target of choice. Several drugs have already made a significant impact in treating both solid and hematologic malignancies.

Among them, idelalisib (Zydelig) stands out as a PI3K-δ inhibitor for blood cancers. By blocking this signaling protein, idelalisib slows disease progression in relapsed chronic lymphocytic leukemia (CLL) and follicular lymphoma.

For solid tumors, everolimus (Afinitor) has carved a place as a potent mTOR inhibitor, disrupting the cellular pathways that accelerate tumor growth. It has been widely used to treat advanced breast cancer (HR+/HER2-), kidney cancer, and pancreatic neuroendocrine tumors.

Here are a couple of promising candidates in the PI3K/AKT/mTOR inhibitor category.

Noteworthy PI3K, AKT, and mTOR inhibitors currently in development

RLY-2608

• Developer: Relay Therapeutics
• Target:  PI3K inhibitor
• Indication: Breast cancer
• Stage: Phase 1

Interim data from an early-stage study indicated that RLY-2608, in combination with fulvestrant, extended progression-free survival in patients with PI3K-mutant, advanced breast cancer to an average of 9.2 months.

STX-478

• Developer: Scorpion Therapeutics (to be acquired by Eli Lilly)
• Target:  PI3K inhibitor
• Indication: Breast cancer and other solid tumors
• Stage: Phase 1/2 

In January 2025, Eli Lilly announced plans to acquire Scorpion Therapeutics’ experimental cancer therapy, STX-478, for up to $2.5 billion. 

Kinase inhibition, an ever-growing market in biotechnology 

The kinase inhibitors market is growing significantly and it looks like it will keep this upward trajectory in the years to come. In 2023, the market was valued at approximately $58 billion and is projected to reach nearly $90 billion by 2034.

Despite their success and their improvement, drug resistance remains a challenge that will become more and more important as therapies age. Biotech companies are already developing next-generation kinase inhibitors with enhanced specificity to overcome drug resistance.

Also, multi-kinase inhibitors have an important role to play as they represent a broad approach to cancer treatment. Drugs such as sorafenib, lenvatinib, and cabozantinib demonstrated efficacy across liver, kidney, and thyroid cancers. Ongoing clinical trials continue to explore the potential of new multi-kinase inhibitors.

Kinase inhibitors are an important and dynamic market within biotech – the future of this area will be about developing candidates with enhanced selectivity that could overcome drug resistance. Some interesting approaches include developing inhibitors that precisely target mutant kinases or allosteric inhibitors – new inhibitors that latch onto a different part of the kinase, changing its shape to turn it off, rather than blocking its main activation site.

There is a lot to look forward to in this field that has already provided a lot for oncology and beyond.