The JAK kinase family

The TYK/JAK cell signalling family (TYK2, JAK1, JAK2, JAK3) is important for maintaining a healthy immune system. TYK2 and JAK1 are involved in signalling pathways that are often deregulated in multiple autoimmune diseases, notably psoriasis.

Members of the JAK family are the targets of several marketed and clinical-stage drugs for cancer and autoimmune diseases. In September 2022, the US Food and Drug Administration (FDA) approved Sotyktu™ (deucravacitinib), Bristol Myers Squibb’s first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor, for the treatment of adults with moderate-to-severe plaque psoriasis. This and other compounds targeting TYK2 and TYK2/JAK1 in multiple autoimmune disease types are currently in clinical trials (e.g. Priovant/Pfizer), offering strong clinical validation for these therapeutic targets. These include late- and mid-stage clinical trials of TYK2 and TYK2/JAK1 inhibitors for lupus, ulcerative colitis, Crohn’s disease, dermatomyositis and other autoimmune diseases.

Sareum’s TYK2/JAK1 clinical development candidate molecule, SDC-1801, demonstrates high selectivity for TYK2 and JAK1 kinases (particularly over related JAK2 and JAK3), compelling activity in disease models of psoriasis and rheumatoid arthritis, the potential for once-daily oral dosing and a good early safety profile. Closely related molecules, including SAR-20347, also show good activity in models of inflammatory bowel disease and systemic lupus erythematosus (lupus). These attributes have supported the progression of SDC-1801 into human clinical trials, which commenced in Melbourne, Australia in June 2023, with the trail advancing into the Multiple Ascending Dose stage in September 2023 (subjects being dosed once daily) and a food effect study in November 2023.

Clinical candidate SDC-1801 was nominated from a novel series of compounds designed and identified by Sareum following a rigorous selection process. The company is also completing its assessment of further dual TYK2/JAK1 inhibitors for the potential treatment of certain cancers and/or as a back-up to SDC-1801.

Sareum’s TYK2/JAK1 preclinical development candidate molecule, SDC-1802, demonstrates high selectivity for TYK2 and JAK1 kinases (particularly over related JAK2 and JAK3). SDC-1802 shows compelling efficacy in blocking cancer cell proliferation in cellular and disease models of T-cell acute lymphoblastic leukaemia (T-ALL) and B-cell lymphoma, the potential for once-daily oral dosing and a good early safety profile. In addition, Sareum has generated encouraging evidence to suggest that this molecule can function as cancer immunotherapy by modulating the host’s immune system to block tumour cell proliferation in disease models of certain kidney, colon, skin and pancreatic cancers. Sareum is progressing SDC-1802 through preclinical development and pending satisfactory progress, into human clinical trials. Sareum is also advancing SDC-1801 as a distinct dual TYK2/JAK1 inhibitor for the potential treatment of autoimmune diseases, including psoriasis, rheumatoid arthritis, inflammatory bowel disease and lupus. SDC-1802 has the potential to act as a back-up molecule for these autoimmune indications.

Sareum’s Covid-19 research programme studied the therapeutic potential of SDC-1801 and ability to block an overactive inflammatory response, commonly known as a “cytokine storm” often observed in severe phase Covid-19 patients. The Company was awarded a grant of approximately £174,000 by UK Research & Innovation (“UKRI”) to investigate the therapeutic potential of SDC-1801 in preclinical models of severe phase Covid-19. Results demonstrated a profile that was superior to the anti-inflammatory steroid dexamethasone and similar to baricitinib, a JAK1/JAK2 inhibitor. The Company believes that SDC-1801 could potentially benefit severe-phase Covid-19 patients by blocking signalling along this inflammatory pathway and therefore reducing the ‘cytokine storm’.

The Checkpoint Kinase 1 (Chk1) programme was initiated and advanced into first clinical trials in a collaboration between Sareum, the Institute of Cancer Research and the CRT Pioneer Fund. The clinical candidate drug, SRA737 (formerly CCT245737), is one of the most advanced Chk1 inhibitors in the clinic, is highly selective for Chk1 and is administered orally. Two Phase 1/2 clinical trials for the candidate drug have been completed in genetically selected patients with advanced cancers, conducted by former licence partner, Sierra Oncology:

• a monotherapy study evaluating SRA737 in patients with tumours identified to have genetic aberrations hypothesised to confer sensitivity to Chk1 inhibition, including ovarian, prostate, non-small cell lung, head & neck, anus, and colorectal cancers. For more information click here

• a drug combination study evaluating SRA737 potentiated by low-dose gemcitabine (LDG) in four cancer indications, including ovarian, small cell lung, sarcoma, and cervical/anogenital. For more information on the trial click here

Preliminary safety & efficacy data support further development of SRA737+LDG for the treatment of anogenital cancer. Additionally, preclinical data demonstrates synergy of SRA737 and SRA737+LDG in combinations with immune checkpoint, Wee1, Poly ADP Ribose Polymerase (PARP) and DNA polymerase inhibitors.

Further SRA737 programme details are available here

Sierra Oncology was acquired by GlaxoSmithKline (GSK) in July 2022. Sareum acquired the licence for SRA737 in March 2025.