更新于：2024-11-01

KLK7 x KLK14 x KLK5

更新于：2024-11-01

基本信息

关联

项与 KLK7 x KLK14 x KLK5 相关的药物

SXR-1096

靶点

KLK14 x KLK5 x KLK7

作用机制

KLK14抑制剂 [+2]

在研机构-

原研机构

Sixera Pharma AB初创企业

在研适应症-

非在研适应症

Netherton综合征

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

项与 KLK7 x KLK14 x KLK5 相关的临床试验

CTIS2023-507743-11-00 / Recruiting

A phase I/II, multicenter, randomized, double-blind, placebo within-patient controlled, first-in-human (FIH) Proof of Concept (PoC) study to evaluate the safety and efficacy of topically applied SXR1096 cream in patients with Netherton syndrome (NS) - SXR001

开始日期2022-02-21

申办/合作机构

Sixera Pharma AB初创企业

EUCTR2021-003210-39-AT / Not yet recruiting临床1/2期

A phase I/II, multicenter, randomized, double-blind, placebo within-patient controlled, first-time-in-man (FTIM) Proof of Concept (PoC) study to evaluate the safety and efficacy of topically applied SXR1096 skin cream in patients with Netherton syndrome (NS)

开始日期2022-02-01

申办/合作机构

Sixera Pharma AB初创企业

NCT05211830 / Unknown status临床1/2期

A Phase I/II, Multicenter, Randomized, Double-blind, Placebo Within-patient Controlled, First-in-human (FIH) Proof of Concept (PoC) Study to Evaluate the Safety and Efficacy of Topically Applied SXR1096 Cream in Patients With Netherton Syndrome (NS)

In this phase I/II trial a topical skin cream with the active substance SXR1096 will be tested in patients with Netherton syndroms, a rare inflammatory skin disease. SXR1096 is a specific and potent protease inhibitor that can inhibit the proteases kallikrein 5, 7 and 14 - all recognised as up-regulated and causing the disease state in Netherton syndrome patients. Patients will be treated for one month with active cream and placebo cream at different areas of the skin.

开始日期2021-12-07

申办/合作机构

Sixera Pharma AB初创企业

100 项与 KLK7 x KLK14 x KLK5 相关的临床结果

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100 项与 KLK7 x KLK14 x KLK5 相关的转化医学

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0 项与 KLK7 x KLK14 x KLK5 相关的专利（医药）

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项与 KLK7 x KLK14 x KLK5 相关的文献（医药）

2022-12-31·Cancer Biology & Therapy

Novel specific activity-based probes validate KLK proteases as druggable targets

Letter

作者: Sotiropoulou, Georgia ; Pampalakis, Georgios ; Zingkou, Eleni

Authors read with great interest the recent publication in which the important paper is presented as the first report of activity-based protein profiling (ABPP) selective for individual KLKs in a complex biol. context.A novel KLK7-specific phosphonate activity-based probe (ABP) was reported, which could discriminate KLK7 from other active KLKs.The KLK7-ABP was also modified to a quenched ABP (qABP) to enable monitoring of KLK7 activity in vivo.KLK14-ABP revealed that this protease drives malignant prostate cell migration, a key step in progression of cancer metastasis.Previously, other KLKs, i.e., KLK5 and KLK7 had been validated as drug targets in skin inflammatory diseases in which the implication of KLK proteolytic cascades is well-defined in vivo.

2022-12-14·Science Translational Medicine1区 · 医学

Dual antibody inhibition of KLK5 and KLK7 for Netherton syndrome and atopic dermatitis

1区 · 医学

Article

作者: Li, Hong ; Pappu, Rajita ; Tam, Christine ; Wittwer, Arthur J ; Tyagi, Tulika ; Cai, Hao ; Hernandez-Barry, Hilda ; Yi, Tangsheng ; Lazarus, Robert A. ; Liu, John ; Lin, Wei-Yu ; Tao, Janet ; Yaspan, Brian L. ; Dunlap, Debra ; Balazs, Mercedesz ; Jackman, Janet K. ; Chen, Emily ; Li, Jing ; Sudhamsu, Jawahar ; Yin, Jianping ; Chiu, Cecilia P.C. ; Zhang, Juan ; Sun, Yonglian ; Loyet, Kelly M. ; Austin, Cary D. ; Chavarria-Smith, Joseph ; Koerber, James T. ; Ghodge, Swapnil V. ; Hackney, Jason A. ; Lee, Wyne P. ; Morton, William D. ; Arron, Joseph R. ; Maun, Henry R.

The epidermis is a barrier that prevents water loss while keeping harmful substances from penetrating the host. The impermeable cornified layer of the stratum corneum is maintained by balancing continuous turnover driven by epidermal basal cell proliferation, suprabasal cell differentiation, and corneal shedding. The epidermal desquamation process is tightly regulated by balance of the activities of serine proteases of the Kallikrein-related peptidases (KLK) family and their cognate inhibitor lymphoepithelial Kazal type–related inhibitor (LEKTI), which is encoded by the serine peptidase inhibitor Kazal type 5 gene. Imbalance of proteolytic activity caused by a deficiency of LEKTI leads to excessive desquamation due to increased activities of KLK5, KLK7, and KLK14 and results in Netherton syndrome (NS), a debilitating condition with an unmet clinical need. Increased activity of KLKs may also be pathological in other dermatoses such as atopic dermatitis (AD). Here, we describe the discovery of inhibitory antibodies against murine KLK5 and KLK7 that could compensate for the deficiency of LEKTI in NS. These antibodies are protective in mouse models of NS and AD and, when combined, promote improved skin barrier integrity and reduced inflammation. To translate these findings, we engineered a humanized bispecific antibody capable of potent inhibition of human KLK5 and KLK7. A crystal structure of KLK5 bound to the inhibitory Fab revealed that the antibody binds distal to its active site and uses a relatively unappreciated allosteric inhibition mechanism. Treatment with the bispecific anti-KLK5/7 antibody represents a promising therapy for clinical development in NS and other inflammatory dermatoses.

2021-09-01·Journal of Investigative Dermatology

A Potent and Selective Kallikrein-5 Inhibitor Delivers High Pharmacological Activity in Skin from Patients with Netherton Syndrome

Article

作者: Gael Krysa ; Ann L. Walker ; Gary Thripp ; Didier Grillot ; Yichen Wang ; Lionel Trottet ; Kathrine J. Smith ; Edwige Nicodeme ; Ryan Bingham ; Simon A. Ward ; Veronique Beneton ; Alexis Denis ; Brandon Santiago ; Alain Hovnanian ; Duncan S. Holmes ; Mark Lennon ; John Liddle ; Jenni Cryan ; Alan Ferrie ; Eloisa Brook ; Anne Bouillot ; Emma Edgar ; Matthew Benson ; Anne-Benedicte Boullay ; Alexandre Moquette ; Steve Wilson ; Ashleigh Howes ; Fiona McClure ; Marie-Helene Fouchet ; Andrew C. Pearce ; James H. Thorpe ; Leandro Santos ; Alain Laroze

Regulation of proteolytic activity in the skin plays a pivotal role in epidermal homeostasis. This is best exemplified in Netherton syndrome, a severe genetic skin condition caused by loss-of-function mutations in the gene serine protease inhibitor Kazal-type 5 encoding lympho-epithelial Kazal-type-related inhibitor, a serine protease inhibitor that regulates kallikrein (KLK)-related peptidase 5, 7, and 14 activities. KLK5 plays a central role in stratum corneum shedding and inflammatory cell signaling, activates KLK7 and KLK14, and is therefore an optimal therapeutic target. We aimed to identify a potent and selective small-molecule inhibitor of KLK5 amenable to epidermal delivery. GSK951 was identified using a structure-based design strategy and showed a half maximal inhibitory concentration of 250 pM for KLK5 and greater than 100-fold selectivity over KLK7 and KLK14. Cocrystal structure analysis identified the critical catalytic site interactions to a surrogate for KLK5. Topical application of GSK951-containing cream inhibited KLK5 activity in TgKLK5 mouse skin, reduced transepidermal water loss, and decreased proinflammatory cytokine expression. GSK951 achieved high concentrations in healthy human epidermis following topical application in a cream formulation. Finally, KLK5 protease activity was increased in stratum corneum of patients with Netherton syndrome and significantly inhibited by GSK951. These findings unveil a KLK5-specific small-molecule inhibitor with a high therapeutic potential for patients with Netherton syndrome.