Introduction
CHM-081 is a synthetic small‑molecule compound that has attracted significant attention in the field of oncology for its potent inhibition of the cyclin‑dependent kinase 4/6 (CDK4/6) family. The designation CHM-081 originates from the Corporate Human Medicine (CHM) laboratory’s internal code for the 81st lead compound identified in a high‑throughput screening campaign targeting the Rb pathway. Since its initial discovery in 2012, CHM-081 has progressed through extensive preclinical evaluation and has entered Phase II clinical trials for the treatment of hormone‑receptor‑positive, HER2‑negative breast cancer. The compound has also been investigated for activity against other malignancies, including pancreatic ductal adenocarcinoma and glioblastoma multiforme, due to its selective inhibition of CDK4/6 and downstream suppression of E2F transcription factors.
Discovery and Development
High‑throughput Screening
In 2012, the CHM research team conducted a high‑throughput screen of 1.2 million synthetic molecules against the ATP‑binding pocket of CDK4/6. The screen employed a fluorescence polarization assay measuring displacement of a labeled ATP analog. CHM-081 emerged as a top candidate, exhibiting an IC₅₀ of 12 nM against CDK4 and 9 nM against CDK6 in cell‑free assays. Subsequent counterscreens against related kinases, such as CDK2 and CDK1, demonstrated a selectivity window of >100‑fold, indicating minimal off‑target kinase inhibition.
Lead Optimization
Lead optimization efforts focused on improving metabolic stability and pharmacokinetic properties while preserving potency and selectivity. Structural modifications included the introduction of a 4‑pyridyl ring and optimization of the hinge‑binding motif. A series of analogs was synthesized, and CHM-081 was selected as the lead candidate based on a combination of favorable in vitro ADMET characteristics and the absence of reactive functional groups that could lead to covalent binding or off‑target toxicity. The synthesis of CHM-081 was achieved through a modular two‑step process that involved a Suzuki‑Miyaura coupling followed by a reductive amination step, yielding a scalable route suitable for preclinical and early clinical production.
Chemical Structure and Synthesis
Molecular Features
CHM-081 possesses a core aminopyrimidine scaffold that engages the hinge region of CDK4/6. The 6‑position of the pyrimidine ring is substituted with a 4‑pyridyl group, providing additional hydrophobic interactions within the binding pocket. An N‑piperidinyl side chain extends into the ATP‑binding cleft, enhancing potency through a hydrogen bond network with the kinase’s backbone amide. The overall molecular formula is C₁₆H₁₇N₅, and the compound has a molecular weight of 307.32 g/mol.
Synthetic Route
The synthesis of CHM-081 begins with 2‑amino‑4‑chloro‑pyrimidine, which undergoes a Suzuki‑Miyaura coupling with 4‑pyridylboronic acid in the presence of Pd(PPh₃)₄ and K₂CO₃ to form 2‑amino‑4‑(4‑pyridyl)pyrimidine. The resulting intermediate is subjected to a reductive amination with piperidine and NaBH₃CN, producing the final product in 78% overall yield. The synthesis avoids the use of toxic reagents and produces minimal waste, aligning with the CHM laboratory’s commitment to green chemistry principles. The scalable route has been transferred to a cGMP‑grade facility for clinical supply.
Pharmacodynamics
Target Interaction
CHM-081 exerts its therapeutic effect by competitively binding to the ATP‑binding site of CDK4 and CDK6. X‑ray crystallography data reveal that the compound adopts an extended conformation, with the aminopyrimidine moiety forming a hydrogen bond with the hinge residue Glu81 in CDK4 and Glu86 in CDK6. The 4‑pyridyl group occupies a lipophilic pocket, while the piperidinyl side chain extends toward the catalytic lysine, thereby inhibiting the kinase’s catalytic activity. The inhibition constant (K_i) values are 9 nM for CDK4 and 7 nM for CDK6, indicating high affinity.
Cellular Activity
In vitro studies using MCF‑7 breast cancer cells demonstrate that CHM-081 reduces phosphorylation of the retinoblastoma protein (Rb) in a dose‑dependent manner, with an effective concentration (EC₅₀) of 30 nM. This phosphorylation blockade leads to G₁ cell‑cycle arrest and subsequent apoptosis in hormone‑receptor‑positive cell lines. Flow cytometry analysis shows a significant accumulation of cells in the G₁ phase at 72 hours post‑treatment. Importantly, CHM-081 displays negligible cytotoxicity against non‑malignant mammary epithelial cells (MCF‑10A) at concentrations up to 10 µM, underscoring its therapeutic index.
Pharmacokinetics
Absorption
Oral bioavailability of CHM-081 has been evaluated in rodent models. Following a single 10 mg/kg dose, plasma concentrations peak at approximately 0.5 hours with a C_max of 1.2 µg/mL. The apparent oral bioavailability is estimated at 45% relative to intravenous administration, attributable to moderate intestinal permeability and limited first‑pass metabolism. Formulation studies using a self‑emulsifying drug delivery system (SEDDS) have further improved absorption, raising C_max to 2.1 µg/mL and extending T_max to 1.5 hours.
Distribution
Distribution studies indicate a volume of distribution (V_d) of 3.5 L/kg in mice, suggesting moderate tissue penetration. CHM-081 demonstrates high plasma protein binding (~88%) primarily to albumin. Tumor uptake studies in a MCF‑7 xenograft model reveal a tumor/plasma ratio of 0.65 at 4 hours post‑dose, indicating adequate penetration into tumor tissue.
Metabolism and Excretion
Metabolite profiling identifies two major routes: N‑dealkylation of the piperidine side chain and hydroxylation of the pyridyl ring. The primary metabolite, CHM-081‑OH, retains modest CDK4/6 inhibitory activity (IC₅₀ ≈ 150 nM). Renal clearance accounts for 55% of the total clearance, while hepatic metabolism contributes the remaining 45%. The compound’s half‑life (t_½) is 4.8 hours in rats, which aligns with the once‑daily dosing schedule employed in preclinical efficacy studies.
Preclinical Studies
In Vivo Efficacy
Murine xenograft models of hormone‑receptor‑positive breast cancer (MCF‑7 and T47D) have been used to evaluate antitumor efficacy. Daily oral administration of CHM-081 at 20 mg/kg reduced tumor volume by 78% relative to vehicle after 21 days of treatment, with no observed weight loss or clinical signs of toxicity. In a genetically engineered mouse model of pancreatic ductal adenocarcinoma (KPC), a combination of CHM-081 with gemcitabine led to a 65% reduction in tumor burden compared to gemcitabine alone.
Combination Therapies
Synergistic interactions between CHM-081 and endocrine agents such as fulvestrant were investigated. In vitro combination indices (CI) calculated using the Chou–Talalay method demonstrated CI values
Safety Pharmacology
Toxicology studies in rats and dogs encompassed a 28‑day repeated‑dose regimen. No adverse effects were noted at doses up to 200 mg/kg/day in rats or 120 mg/kg/day in dogs, with no clinical chemistry abnormalities or histopathologic findings. Cardiac safety assessment using the hERG assay revealed an IC₅₀ >10 µM, indicating a low risk of QT prolongation. A 3‑month toxicology study in non‑human primates demonstrated no immunotoxicity or off‑target effects, supporting progression to human trials.
Clinical Trials
Phase I: Dose‑Escalation
Phase I trials enrolled 42 patients with advanced solid tumors, evaluating safety, tolerability, and pharmacokinetics of escalating oral doses of CHM-081. The maximum tolerated dose (MTD) was established at 100 mg once daily, with dose‑limiting toxicities (DLTs) consisting of grade 3 neutropenia and grade 2 fatigue at 120 mg/day. Pharmacokinetic parameters in humans mirrored preclinical findings, with a mean t_½ of 5.2 hours and a C_max of 1.8 µg/mL at the 100 mg dose. Preliminary evidence of antitumor activity was observed in two patients with metastatic breast cancer, each achieving stable disease for >6 months.
Phase II: Efficacy in Breast Cancer
A multicenter, open‑label Phase II study enrolled 156 patients with metastatic hormone‑receptor‑positive, HER2‑negative breast cancer. Patients received CHM-081 at 100 mg daily in combination with standard endocrine therapy. The primary endpoint, progression‑free survival (PFS), showed a median of 9.4 months compared to 6.3 months in a matched historical cohort (HR 0.68, 95% CI 0.53–0.87). Objective response rate (ORR) was 22%, and disease control rate (DCR) reached 68%. Safety data revealed that grade ≥3 adverse events occurred in 14% of patients, predominantly neutropenia and anemia, both manageable with dose interruptions and supportive care.
Phase III: Comparative Trial
A randomized, double‑blind Phase III trial is underway, comparing CHM-081 plus endocrine therapy versus fulvestrant monotherapy in the first‑line setting for metastatic hormone‑receptor‑positive breast cancer. Interim analyses at 12 months indicate a statistically significant improvement in PFS for the CHM-081 arm (HR 0.65, 95% CI 0.48–0.89). The trial also assesses overall survival, safety, and patient‑reported outcomes. Enrollment is projected to complete by Q4 2028, with final results expected early 2030.
Regulatory Status
Investigational New Drug (IND) Approval
CHM-081 received IND approval from the U.S. Food and Drug Administration (FDA) in September 2019, enabling the initiation of Phase I trials. The IND filing included extensive preclinical data, a cGMP synthesis protocol, and a detailed clinical protocol. The FDA reviewed the IND in accordance with the Investigational New Drug regulations, approving the study without condition.
Orphan Drug Designation
In March 2021, CHM-081 was granted orphan drug status for metastatic hormone‑receptor‑positive breast cancer by the FDA and the European Medicines Agency (EMA). This designation provides incentives such as seven years of market exclusivity in the United States and five years in the European Union, contingent upon regulatory approval. The orphan status also facilitates accelerated review pathways and potential priority listing.
Clinical Trial Registration
All clinical trials involving CHM-081 are registered with ClinicalTrials.gov, ensuring transparency and compliance with global regulatory requirements. Trial identifiers include NCT03456789 (Phase I), NCT03912345 (Phase II), and NCT04198765 (Phase III). The registration information includes detailed study designs, inclusion/exclusion criteria, and safety monitoring plans.
Applications and Potential
Oncologic Indications
- Hormone‑receptor‑positive, HER2‑negative metastatic breast cancer (current indication in clinical development).
- Triple‑negative breast cancer, where preclinical models indicate sensitivity to CDK4/6 inhibition in combination with immunotherapy.
- Pancreatic ductal adenocarcinoma, with evidence of synergy between CHM-081 and chemotherapeutic agents such as gemcitabine.
- Glioblastoma multiforme, where blood–brain barrier penetration studies suggest potential for targeting the Rb pathway in this aggressive malignancy.
Non‑Oncologic Uses
Preliminary research explores the role of CDK4/6 in cardiovascular biology, suggesting that CHM-081 may influence cardiac remodeling post‑myocardial infarction. Additionally, studies in autoimmune disease models point to potential therapeutic benefits in conditions such as systemic lupus erythematosus, where aberrant cell‑cycle progression contributes to disease pathology.
Safety and Toxicology
Hematologic Toxicity
Neutropenia and anemia constitute the most common hematologic adverse events. In the Phase II trial, grade 3 neutropenia occurred in 6% of patients, managed with dose modifications and granulocyte‑stimulating factor support. Hematologic recovery was typically observed within 7–10 days following dose interruption.
Gastrointestinal Effects
Fatigue, nausea, and diarrhea were reported, with grade 2 or lower severity in >80% of patients. No clinically significant differences were noted between the CHM-081 and placebo groups in terms of gastrointestinal tolerability.
Off‑Target Safety
Comprehensive off‑target profiling, including kinase panel assays, indicated minimal cross‑reactivity. The hERG assay produced an IC₅₀ >10 µM, mitigating concerns about cardiac arrhythmias. Neurological safety assessment using rotarod and open‑field tests in rodents found no motor deficits or altered locomotor activity.
Conclusion
CHM-081 represents a promising CDK4/6 inhibitor with a robust preclinical and clinical profile. Its selective inhibition of Rb phosphorylation translates into effective antitumor activity, particularly in hormone‑receptor‑positive breast cancer. Ongoing Phase III trials will determine its comparative efficacy and establish its place in the therapeutic landscape. The regulatory pathway, including orphan drug designation and IND approval, underscores the translational potential of CHM-081 and provides a framework for future drug development endeavors.
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