Major Breakthrough! These Targets Entered Clinical Trials for the First Time in 2025

In the long journey of new drug development, a drug’s first entry into clinical trials is undoubtedly a highly significant milestone. Behind this achievement lies the completion of extensive biological validation—including gene expression, protein structure, and functional assays—of the relevant targets. These targets are very likely to play key roles in the pathogenesis of their corresponding diseases, bringing new hope for conquering these illnesses. Today, we focus on two important targets that emerged in March and entered clinical trials for the first time: ACK1 and CD83, and explore how they are leading pharmaceutical innovation.

ACK1: A New Dawn for Prostate Therapy?

ACK1 (Activated Cdc42-associated kinase 1), also known as TNK2, is a non-receptor tyrosine kinase encoded by the TNK2 gene. It can interact with multiple receptor tyrosine kinases—such as EGFR, MERTK, HER2, PDGFR, and the insulin receptor—and transmit extracellular signals by phosphorylating downstream effectors (e.g., AKT), thereby regulating various oncogenic signaling events across multiple tumor types.

ACK1 kinase plays pivotal roles in cancer development and drug resistance. In prostate cancer, ACK1 promotes AR nuclear translocation and transcriptional activation, enhances castration resistance, and suppresses the AR-inhibitory long noncoding RNA NXTAR, offering new strategies for CRPC treatment. In breast cancer, ACK1 drives transcription of cell-cycle genes, leading to CDK4/6 inhibitor resistance; its knockout inhibits tumor growth in TNBC. In lung cancer, ACK1 fosters tumor progression and resistance via STAT3, AKT, and MAPK signaling. In colorectal and gastric cancers, TNF-α activates ACK1 to enhance AKT signaling and regulate epithelial–mesenchymal transition. In hematologic malignancies, ACK1 regulates MAPK signaling via SHP2 phosphorylation and is associated with CSF3R mutations.

ACK1 also exerts oncogenic functions in hepatocellular carcinoma, osteosarcoma, and glioma, and is overexpressed or amplified in multiple cancers—including prostate, breast, non-small cell lung, glioma, ovarian, pancreatic, and colorectal cancers.

In immune regulation, ACK1 inhibits T cell activation. It phosphorylates CBP/PAG and CSK (pY18-CSK), enhancing CSK activity and thereby restraining T cell activation. In CRPC patients treated with immune checkpoint blockade (ICB), the ACK1/pY18-CSK pathway is reactivated, leading to ICB resistance. ACK1 knockout or pharmacological inhibition can overcome ICB tolerance, suggesting that ACK1 inhibitors may synergize with ICB in treating resistant solid tumors.

(R)-9b: The Rising Star of Prostate Cancer Therapy

(R)-9b is under intensive commercial development by TechnoGenesys. Its origins date back to 2017, when researchers at the Moffitt Cancer Center first reported (R)-9b in Cancer Cell. That study revealed a key mechanism: ACK1 (TNK2) phosphorylates histone H4 at tyrosine 88 (pY88-H4) on the AR promoter, recruiting the WDR5/MLL2 complex and triggering H3K4 trimethylation. This epigenetic cascade enhances transcription of AR and its splice variant AR-V7, driving progression to castration-resistant prostate cancer (CRPC) and maintaining its malignancy. The ACK1 inhibitor (R)-9bMS acts like a “brake,” reversing pY88-H4 modification to resensitize CRPC cells to androgen deprivation, lowering AR/AR-V7 levels, and effectively inhibiting tumor growth.

In June 2022, the same team published groundbreaking findings in Science Translational Medicine, uncovering the mechanism of enzalutamide resistance in CRPC. They showed that AR acetylation at lysine 609 in its zinc-finger DNA binding domain (acK609-AR) allows AR to evade enzalutamide inhibition, enter the nucleus, and activate escape transcriptional programs. Further investigation revealed that ACK1-mediated phosphorylation of AR at tyrosine 267 is required for subsequent K609 acetylation, forming a positive feedback loop that amplifies AR and ACK1 expression, accelerating CRPC progression and resistance. Notably, the ACK1 inhibitor (R)-9b precisely blocks AR Y267 phosphorylation, suppresses K609 acetylation, and significantly inhibits growth of enzalutamide-resistant CRPC tumors.

In December 2022, researchers published new results in Nature Communications, discovering that ACK1 phosphorylates CSK at tyrosine 18 (pY18-CSK), enhancing CSK activity and suppressing T cell activation, thereby inducing ICB resistance. Tnk2 knockout mice exhibited reduced CSK Y18 phosphorylation and spontaneous activation of CD8+ and CD4+ T cells, suppressing ICB-resistant tumor growth. In CRPC patients receiving ICB, the ACK1/pY18-CSK pathway was reactivated, confirming its key role in ICB tolerance. Importantly, (R)-9b also inhibited growth of ICB-resistant tumors, paving a new path to overcome ICB resistance and potentially expand ICB therapies.

As of March 2025, TechnoGenesys has officially launched the Phase I clinical trial of (R)-9b. This trial aims to evaluate the safety and tolerability of (R)-9bMS in patients with metastatic castration-resistant prostate cancer. Thirty patients will be enrolled, each taking oral doses of (R)-9b twice daily for up to six months. Data are expected to be released in March 2026, which will further clarify the clinical potential of (R)-9b.

Prostate cancer is the second most common cancer among men worldwide. In 2022, there were approximately 1.46 million new diagnoses globally, underscoring the serious threat to male health. In the course of disease progression, CRPC is especially challenging. Some 10–20% of patients receiving androgen deprivation therapy (ADT) relapse to CRPC within two to three years, greatly increasing treatment difficulty and adversely affecting prognosis.

From a market perspective, Grand View Research estimates that the global CRPC market reached USD 12.9 billion in 2024 and is projected to grow at a compound annual growth rate (CAGR) of 8.7% over the next five years. This growth reflects immense demand for CRPC therapies, which, given population aging and rising prostate cancer incidence, is only intensifying.

Current CRPC treatments are diverse. Chemotherapy with docetaxel is a first-line option, yielding a median overall survival (mOS) of 19.2 months but burdened by significant side effects that impair quality of life. AR-targeted therapies, such as enzalutamide administered after docetaxel progression, achieve an mOS of 18.4 months, yet nearly all patients eventually develop resistance. Among other targeted options, PARP inhibitors as third-line monotherapy post-AR therapy (e.g., olaparib) achieve an mOS of 18.5 months; combined first-line therapy of abiraterone plus olaparib reaches an mOS of 42.1 months. While these options extend survival, their limitations highlight the urgent need for novel agents capable of delivering superior efficacy in clinical trials.

To date, two specific ACK1 inhibitors have entered development: TechnoGenesys’s (R)-9b and Sichuan University’s 21-a. Among these, (R)-9b leads the field and faces relatively minimal competition.

CD83: A Potential Leukemia Target

CD83 is a member of the immunoglobulin superfamily, primarily expressed on the surface of mature dendritic cells (DCs), activated B cells, and T cells. It exists in two forms: membrane-bound (mCD83) and soluble (sCD83), with mCD83 serving as a marker for mature DCs. CD83 plays an important role in immune responses, acting as a co-stimulatory molecule to promote the activation of T and B cells, and it also participates in regulating inflammation and maintaining immune tolerance. Moreover, sCD83 has shown therapeutic potential in some disease models, such as in rheumatoid arthritis and inflammatory bowel disease, where it can alleviate inflammation by regulating cytokine levels and inducing regulatory T cells.

Based on GEPIA data, CD83 shows higher specific expression in diffuse large B-cell lymphoma (DLBC). Additionally, in recent studies, CD83 has also been found to be specifically expressed in acute myeloid leukemia (AML) and breast cancer (BC).

CD83 CAR-T Therapy: New Hope for Acute Myeloid Leukemia Treatment

In the field of cancer treatment, CAR-T cell therapy has gradually emerged as a powerful weapon in the fight against cancer. Among these, CAR-T therapy targeting CD83 has attracted much attention in recent years, particularly in the treatment of acute myeloid leukemia (AML), where it has made significant progress.

Roswell Park Comprehensive Cancer Center, a pioneer in this field, has advanced autologous anti-CD83 CAR-T therapy to Phase I clinical trials for the treatment of relapsed or refractory AML. The trial plans to recruit 26 patients and aims to evaluate the safety and preliminary efficacy of this therapy. This initiative offers new hope for AML patients for whom traditional treatment methods have been ineffective.

In February of this year, Roswell Park Cancer Center also published preclinical research results on CD83 CAR-T therapy for breast cancer. The study showed that CD83 CAR-T cells successfully eradicated LM2 tumors in NSG mice within the first week after infusion. Compared to mice that received only untreated (UT) or LM2 tumors, those treated with CD83 CAR-T therapy showed significantly reduced LM2 BLI radiance. These preclinical results not only demonstrate the potential of CD83 CAR-T in breast cancer treatment but also provide strong theoretical support for its application in other cancer types.

Acute myeloid leukemia (AML) is a severe hematologic malignancy. In 2021, there were approximately 140,000 new cases of AML worldwide, with a relapse rate of 35%-85%. Relapsed refractory AML is highly heterogeneous, with a poor prognosis for patients, with a 5-year survival rate of only about 10%. Current treatment options recommended by clinical guidelines include FLT3 inhibitors, IDH inhibitors, and BCL-2 inhibitors, but these drugs still cannot meet all patient needs, making the development of more effective treatment methods urgent.

From a market perspective, the global market for AML treatment is showing a favorable growth trend. In 2024, the global AML treatment market is expected to reach $3.47 billion, and it is projected to continue growing at a compound annual growth rate (CAGR) of 10.6% from 2025 to 2030. This growth trend reflects the huge demand for effective treatment solutions for AML patients and provides strong market drive for the research and development of related therapeutic technologies and drugs.

Regarding the competitive landscape, the focus on CD83 as a target is currently relatively limited, with most participants being non-profit organizations, including Chongqing Daping Hospital and Moffitt Research Center. In this competition, Roswell Park Comprehensive Cancer Center holds a leading position in the CD83 CAR-T therapy field with its advanced clinical trial progress. With further research and clinical trial advancements, CD83 CAR-T therapy is expected to break the current AML treatment landscape and provide more effective treatment options for patients.

Conclusion

In the journey of new drug development, ACK1 and CD83, which entered clinical trials for the first time in March, have attracted significant attention. ACK1 plays a key role in various cancers, and its inhibitor (R)-9b has moved from basic research to Phase I clinical trials. If its efficacy is ideal, it has the potential to revolutionize cancer treatment and break the current dilemma of castration-resistant prostate cancer (CRPC). CD83, as a key immune-regulatory target, has seen its CAR-T therapy advanced to Phase I clinical trials by Roswell Park Comprehensive Cancer Center. If successful, it will rewrite the treatment landscape of AML. These two targets hold the hope of patients and are expected to lead pharmaceutical innovation, driving the industry to new heights.

For newcomers, the following core opportunities exist: ACK1's advantage lies in its deep mechanisms and combination value, while CD83's advantage lies in its novelty as a target and clinical urgency. Pharmaceutical companies can leverage their pipeline advantages to choose rapid clinical translation (such as CD83 CAR-T) or long-term multidimensional development (such as ACK1 across cancer types + combination therapies) to seize high ground in niche fields.

Reference

[1]. ACK1/TNK2 kinase: molecular mechanisms and emerging cancer therapeutics
[2]. ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer
[3]. Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance
[4]. grand view research
[5]. GEPIA
[6]. CD83 Expression By Human Breast Cancer Mediates Effective Killing By CAR T