milciclib (TZLS-201) / Nerviano Medical Sciences, Tiziana Life Sci - LARVOL DELTA

Ubiquitin-specific Peptidase 53 Suppresses Head/Neck Tumorigenesis by Stabilizing FBXW7. (PubMed, Anticancer Res) - "USP53 functions as a critical tumor suppressor in HNSC by post-translationally stabilizing the E3 ubiquitin ligase FBXW7. This molecular mechanism establishes a targetable cell-cycle vulnerability sensitive to cyclin-dependent kinase inhibitors and uncovers a direct connection between deubiquitinase activity and tumor immune cell infiltration."

IO biomarker • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Targeted Protein Degradation • FBXW7 • USP5

A patent review of cyclin-dependent kinase 5 (CDK5) inhibitors (1999-2025). (PubMed, Front Bioeng Biotechnol) - "We examine the chemical diversity, selectivity profiles, and therapeutic claims of major chemotypes, including purine analogs (e.g., roscovitine), pyrazole derivatives (e.g., dinaciclib, milciclib), indolobenzazepinones, indirubin derivatives, and emerging modalities such as peptides. Furthermore, we discuss major obstacles such as overcoming off-target toxicity against other CDKs, ensuring sufficient CNS exposure, and identifying reliable biomarkers. Lastly, we speculate on how future success will depend on new strategies such as p25-specific modulation, targeted protein degradation, and advanced delivery systems to translate CDK5' therapeutic potential into the clinic."

Journal • Review • CNS Disorders • Oncology • Targeted Protein Degradation

Cyclin-dependent kinase-inhibitor screening and structural analysis identify a CDK-like kinase candidate in Naegleria fowleri. (PubMed, Parasit Vectors) - "This study identified multiple CDK inhibitor scaffolds with potent in vitro activity against N. fowleri and supports Nf_CDK-like protein1 as a plausible CDK-like kinase target candidate through integrated phenotypic and structure-based analyses, with direct biochemical validation needed in future studies. These findings suggest that CDK-like pathways may represent a relevant molecular axis in N. fowleri and provide a basis for future structure-guided optimization of anti-amoebic candidates."

Journal • CNS Disorders • Infectious Disease • CDK1 • CDK9

Investigating the synergistic effect of milciclib and PD0325901 in colorectal cancer therapy (AACR 2024) - "The discovery of the down-regulation of these proteins and pathways after treatment provides a molecular basis to elucidate the synergistic mechanism underlying Milciclib and PD0325901 combination therapy. In conclusion, our study establishes the combinatorial use of Milciclib and PD0325901 as a potential breakthrough in the treatment of colorectal cancer, offering a promising prospect for enhancing future patient outcomes."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Synergistic anticancer effects of milciclib and mirdametinib: mechanistic insights into cell cycle arrest, DNA damage, and senescence (AACR 2025) - "These findings highlight the complementary mechanisms of action of Milciclib and Mirdametinib. The synergy observed in this combination therapy provides a strong rationale for further clinical investigation."

Colorectal Cancer • Oncology • Solid Tumor • CDKN1A • HRD • RAD51

Spatial proteo-transcriptomic profiling reveals the molecular landscape of borderline ovarian tumors and their invasive progression. (PubMed, Cancer Cell) - "We functionally validated 16 drug targets identified through integrated spatial transcriptomics and proteomics. Combined treatment targeting CDK4/6 (milciclib) and FOLR1 (mirvetuximab) achieved significant tumor reduction in vivo, representing a promising therapeutic strategy for LGSC."

Journal • Oncology • Ovarian Cancer • Solid Tumor • CDK4 • FOLR1 • MET

Milciclib-mediated CDK2 inhibition to boost radiotherapy sensitivity in colorectal cancer. (PubMed, Front Pharmacol) - "It disrupts the G2/M checkpoint and impairs DNA repair mechanisms. These findings suggest that Milciclib has the potential to be an effective therapeutic agent for CRC."

Journal • Colorectal Cancer • Oncology • Solid Tumor • RAD51

Milciclib-mediated CDK2 inhibition to boost radiotherapy sensitivity in colorectal cancer (Front Pharmacol) - "When combined with irradiation, Milciclib led to a 20% increase in the proportion of cells in the G1 phase and a 10% decrease in the G2 phase, suggesting an alteration in cell cycle distribution....In radiation-resistant CRC cells, the combination of Milciclib and irradiation demonstrated increased efficacy, with a sensitizer enhancement ratio (SER) above 1, indicating a potential radiosensitizing effect."

Preclinical • Colorectal Cancer

IFIH1-mediated post-transcriptional regulation of PTTG1 promotes proliferation and affects PHA-848125 sensitivity and prognosis in oropharyngeal carcinoma. (PubMed, Am J Cancer Res) - "We found that the IFIH1-PTTG1 axis could regulate the PHA-848125 response and functionally mediate inter-individual oropharyngeal cancer susceptibility and prognosis. This study aimed to confirm the upstream regulatory genes of PTTG1 and further investigate the specific interactions in this signaling pathway, which will provide a new approach for the treatment of oropharyngeal carcinoma."

Journal • Endocrine Cancer • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Pituitary Gland Carcinoma • Solid Tumor • IFIH1 • PTTG1

Comprehensive analysis of cuproptosis genes and cuproptosis-related genes as prognosis factors in esophageal squamous cell carcinoma. (PubMed, Genomics) - "The results also showed that milciclib might inhibit the proliferation and migration of KYSE150 and KYSE510 cells by targeting CDKN2A. In conclusion, the abovementioned CUGs and CRGs play a crucial role in tumorigenesis and cancer progression in ESCC, indicating their potential as therapeutic targets."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • BTLA • CDKN2A • DLAT • FDX1 • LIAS • LIPT1 • MFI2 • PDHA1 • PRRX1

Efficacy of milciclib (PHA-848125AC), a pan-cyclin d-dependent kinase inhibitor, in two phase II studies with thymic carcinoma (TC) and B3 thymoma (B3T) patients. (ASCO 2018) - P2; "Oral treatment with milciclib was safe and well-tolerated and met primary and secondary endpoints, achieving disease stabilization in a majority of TC/B3T patients."

Clinical • P2 data • Neuroendocrine Tumor

Tiziana Life Sciences Announces IND filed for Phase 2 Study of Milciclib in Combination with Gemcitabine for Non-Small Cell Lung Cancer (GlobeNewswire) - "Tiziana Life Sciences Ltd...announced the Investigational New Drug (IND) application filing for milciclib in combination with gemcitabine for non-small cell lung cancer (NSCLC)."

IND • Lung Cancer • Non Small Cell Lung Cancer • Oncology

Tiziana Life Sciences Ltd (“Tiziana” or “the Company”) - Updated Interim Results for the Six Months Ended 30 June 2022 (GlobeNewswire) - "Development activity during the first six months ended June 2022:...TZLS-201 - ​Completed the manufacturing of clinical supplies, milciclib capsules, and initiated ICH stability program....Highlights post period end:...On December 15, 2022, Tiziana filed an IND with the FDA pertaining to a Phase 2 study of milciclib in combination with gemcitabine for NSCLC indication. Though further development on milciclb has been paused, the IND filing enables the Company to maximise the asset value with limited additional resources."

Commercial • IND • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

Milciclib in Combination With Gemcitabine in Advanced NSCLC (clinicaltrials.gov) - P2 | N=28 | Not yet recruiting | Sponsor: Tiziana Life Sciences LTD

Combination therapy • New P2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Milciclib: Initiation of P2 trial in combination with gemcitabine for KRAS+ NSCLC in Q1 2022 (Tiziana Life Sciences) - Investor Presentation

New P2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology

Study of Milciclib in Patients With Unresectable/Metastatic Hepatocellular Carcinoma (clinicaltrials.gov) - P2a; N=31; Completed; Sponsor: Tiziana Life Sciences, PLC; Active, not recruiting ➔ Completed

Clinical • Trial completion • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • MRI

Efficacy of milciclib (PHA-848125AC), a pan-cyclin d-dependent kinase inhibitor, in two phase II studies with thymic carcinoma (TC) and B3 thymoma (B3T) patients. (ASCO 2018) - P2; "Oral treatment with milciclib was safe and well-tolerated and met primary and secondary endpoints, achieving disease stabilization in a majority of TC/B3T patients."

Clinical • P2 data • Neuroendocrine Tumor

[VIRTUAL] Phase IIa safety and efficacy of milciclib, a pan-cyclin dependent kinase inhibitor, in unresectable, sorafenib-refractory or -intolerant hepatocellular carcinoma patients. (ASCO 2020) - "Milciclib, acting via a new mechanism, was safe, well-tolerated and met primary and secondary endpoints with 61% CBR. These promising clinical data warrant further evaluation of milciclib. Research Funding: Tiziana Life Sciences"

Clinical • P2a data • Fatigue • Gastrointestinal Cancer • Hematological Disorders • Hepatocellular Cancer • Oncology • Ophthalmology • Pain • Retinal Disorders • Solid Tumor

Pharma Team, to Identify a Partner in Japan and Other Asian Countries for Further Clinical Development of Milciclib in Patients with Advanced Hepatocellular Carcinoma. (GlobeNewswire) - "Tiziana Life Sciences...announces that it has executed an agreement with Takanawa Japan K.K, Pharma Team, (Takanawa) for a strategic business development plan to Identify a clinical partner in Japan and other Asian countries for further clinical development of Milciclib for treatment in advanced hepatocellular carcinoma (HCC) patients."

Licensing / partnership • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology

The role of drug efflux and uptake transporters ABCB1 (P-gp), ABCG2 (BCRP) and OATP1A/1B and of CYP3A4 in the pharmacokinetics of the CDK inhibitor milciclib. (PubMed, Eur J Pharm Sci) - "Thus, ABCB1 and ABCG2 cooperatively limit milciclib brain penetration. The low impact of OATP1 and CYP3A could be clinically favorable for milciclib, reducing the risks of unintended drug-drug interactions or interindividual variation in CYP3A4 activity."

Journal • PK/PD data • Oncology • ABCB1 • ABCG2 • CYP3A4

Milciclib: Initiation of P2b trial for HCC in Q3 2021 (Tiziana Life Sciences) - Investor Presentation: Interim data from P2b trial for HCC in Q2 2022

New P2b trial • P2b data • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology

CDK inhibitor PHA-848125 preferentially inhibits proliferation of triple negative breast cancer and synergizes with cisplatin (AACR 2018) - "A combination treatment of PHA-848125 and cisplatin inhibited tumor growth and induced apoptosis synergistically in vitro and in vivo. Thus, our preclinical experiments set the rationale for the clinical evaluation of PHA-848125, either alone or in combination with cisplatin, for the treatment of TNBC."

HER2 Breast Cancer • Hormone Receptor Breast Cancer • Triple Negative Breast Cancer

[VIRTUAL] Phospho-Proteomic Profiling of T-Cell Acute Lymphoblastic Leukemia Identifies Targetable Kinase Activities and Novel Treatment Combination Strategies (ASH 2020) - "The in vitro drug screening showed an effective response and G1-arrest following treatment with the CDK1/2 inhibitor milciclib in all the cell lines tested, with IC50 values between 10nM and 1uM...Interestingly, the concomitant inhibition of the SRC-family kinases by dasatinib and the INSR/IGF-1R axis by BMS-754807 led to a drastic reduction of cell viability at nanomolar concentrations even in cell lines that did not respond to dasatinib, identifying a novel possible effective combination strategy for T-ALL...Moreover, 70% of our PDXs efficiently responded to the broad spectrum kinase inhibitor midostaurin (IC50 < 1uM), highlighting the importance of targeting multiple signaling nodes simultaneously to tackle T-ALL vulnerabilities. Conclusions Ranking kinase activities and signaling networks from phospho-proteomic data can guide the use of PKIs as treatment option for T-ALL patients. Moreover, kinase activity profiling can provide insights for efficient treatment..."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • ABL1 • CDK1 • IGF1R • IR • NUP214 • PAK1 • ZAP70

Milciclib: Patent expiry related to method of use (multiple indications and combination therapies with cytotoxics) in US, EU, China, Hong Kong and Japan in 2029/2030 (Tiziana Life Sciences) - Corporate Presentation: Patent expiry related to Composition of matter, methods of use and process of manufacturing in US, Europe, Eurasia, Africa, Algeria, Argentina, Australia, Barbados, Bosnia & Herzegovina, Canada, Colombia, Costa Rica, Croatia, Cuba, Ecuador, Georgia, Iceland, India, Indonesia, Israel, Japan, Korea, Kosovo, Malaysia, Mexico, Mongolia, Montenegro, New Zealand, Nicaragua, Norway, Pakistan, Philippines, Serbia, Singapore, South Africa, Sri Lanka, Taiwan, Tunisia, Ukraine, Uzbekistan, Vietnam, Brazil, Egypt, Thailand, Trinidad & Tobago, Venezuela in 2024

Patent • Oncology

Milciclib: Initiation of P2b trial for HCC in Q2 2021 (Tiziana Life Sciences) - Corporate Presentation

New P2 trial • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology