Discovery of JNJ-64264681: A Potent and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase

Tichenor, Mark S.; Wiener, John J. M.; Rao, Navin; Bacani, Genesis M.; Wei, Jianmei; Deckhut, Charlotte Pooley; Barbay, J. Kent; Kreutter, K. D.; Chang, Leon; Clancy, Kathleen W.; Murrey, Heather E.; Wang, Weixue; Ahn, Kay; Huber, Michael; Rex, Elizabeth; Coe, Kevin J.; Wu, Jiejun; Rui, Haopeng; Sepassi, Kia; Gaudiano, Marcello; Bekkers, Mariette; Cornelissen, Ivo; Packman, Kathryn; Seierstad, Mark; Xiouras, Christos; Bembenek, Scott D.; Alexander, Richard; Milligan, Cynthia; Balasubramanian, Sriram; Lebsack, Alec D.; Venable, Jennifer D.; Philippar, Ulrike; Edwards, James P.; Hirst, Gavin C.

doi:10.1021/acs.jmedchem.2c01026

Cited by 5 publications

(5 citation statements)

References 32 publications

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“…34 Bruton's tyrosine kinase (BTK), a member of the Tec family of nonreceptor cytoplasmic tyrosine kinases, plays an essen-tial role in B cell receptor signaling pathways and Fcγ receptor signaling in leukocytes. 35 BTK participated in the regulating of pathways that contribute to rheumatoid arthritis (RA), a multifactorial autoimmune disease. 36 In 2019, Watterson et al reported the discovery of Branebrutinib (60, ►Fig.…”

Section: Improving Pk Properties Of Drug Moleculesmentioning

confidence: 99%

Application of Chiral Piperidine Scaffolds in Drug Design

Chen

Zhang

2023

Pharmaceutical Fronts

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Chiral piperidine scaffolds are prevalent as the common cores of a large number of active pharmaceuticals in medical chemistry. This review outlined the diversity of chiral piperidine scaffolds in recently approved drugs, and also covers the scaffolds in leads and drug candidates. The significance of chiral piperidine scaffolds in drug design is also discussed in this article. With the introduction of chiral piperidine scaffolds into small molecules, the exploration of drug-like molecules can be benefitted from the following aspect: (1) modulating the physicochemical properties; (2) enhancing the biological activities and selectivity; (3) improving pharmacokinetic properties; and (4) reducing the cardiac hERG toxicity. Given above, chiral piperidine-based discovery of small molecules will be a promising strategy to enrich our molecules' library to fight against diseases.

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Section: Improving Pk Properties Of Drug Moleculesmentioning

confidence: 99%

Application of Chiral Piperidine Scaffolds in Drug Design

Chen

Zhang

2023

Pharmaceutical Fronts

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“…Beyond our work, there have been several recent examples of conformational control about a prospective atropisomeric axis to modulate the properties of biologically active small molecules, including Boehringer Ingelheim’s mutant EGFR inhibitors, Lorlatinib, and Grenning’s cannabinol derivatives . More recently, a team at Janssen has disclosed an atropisomeric BTK inhibitor where the configuration of the atropisomeric axis was crucial for activity. , …”

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confidence: 93%

“…27 More recently, a team at Janssen has disclosed an atropisomeric BTK inhibitor where the configuration of the atropisomeric axis was crucial for activity. 28,29 Herein we describe studies where we evaluated analogues of ibrutinib where the CEP of the 3-aryl−aryl axis is shifted to more orthogonal conformations by the addition of methyl groups adjacent to this axis. These simple perturbations led to large improvements in BTK selectivity with little effect on BTK potency.…”

mentioning

confidence: 99%

Controlling Ibrutinib’s Conformations about Its Heterobiaryl Axis to Increase BTK Selectivity

Toenjes

Heydari²,

Albright³

et al. 2023

ACS Med. Chem. Lett.

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Ibrutinib is a covalent BTK inhibitor that is approved for several indications in oncology. Ibrutinib possesses significant off-target activities toward many kinases, often leading to adverse events in patients. While there have been robust medicinal chemistry efforts leading to more selective second-generation BTK inhibitors, there remains a need for new strategies to rapidly improve the selectivity of kinase inhibitors. An analysis of PDB data revealed that ibrutinib binds BTK in dihedral conformations that are orthogonal of ibrutinib's predicted low energy conformational range. Synthesis of a series of analogues with ground state conformations shifted toward orthogonality led to the discovery of an analogue with two incorporated ortho-methyl groups that possessed markedly increased BTK selectivity. This work suggests that conformational control about a prospective atropisomeric axis represents a strategy to rapidly program a compound's selectivity toward a given target.

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“…From preclinical pharmacokinetic (PK) studies in rats and dogs, JNJ-64264681 has a short drug half-life (<2 hours), considered desirable for the development of a covalent drug, attributable to both a moderate clearance and volume of distribution. 10 In unpublished data, it is highly permeable and subject to efflux through human breast cancer resistance protein and P-glycoprotein. It is highly plasma protein bound across species (>90% bound), with albumin being the major contributor to the human binding.…”

mentioning

confidence: 99%

“…JNJ‐64264681 is being developed as an orally active, covalent, and irreversible BTK inhibitor as a potential treatment for patients with B‐cell malignancies or autoimmune disorders. From preclinical pharmacokinetic (PK) studies in rats and dogs, JNJ‐64264681 has a short drug half‐life (<2 hours), considered desirable for the development of a covalent drug, attributable to both a moderate clearance and volume of distribution 10 . In unpublished data, it is highly permeable and subject to efflux through human breast cancer resistance protein and P‐glycoprotein.…”

mentioning

confidence: 99%

A Phase 1 First‐in‐Human Pharmacokinetic and Pharmacodynamic Study of JNJ‐64264681, a Covalent Inhibitor of Bruton's Tyrosine Kinase

Leu

Miao

Shalayda

et al. 2023

Clinical Pharm in Drug Dev

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JNJ-64264681 is an irreversible covalent inhibitor of Bruton's tyrosine kinase. This phase 1, first-in-human, 2-part (singleascending dose [SAD]; multiple-ascending dose [MAD]) study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD; Bruton's tyrosine kinase occupancy [BTKO]) of JNJ-64264681 oral solution in healthy participants. For SAD (N = 78), 6 increasing doses of JNJ-64264681 (4-400 mg) or placebo were evaluated in fasted males. The effects of sex, food, and a capsule formulation were evaluated in separate cohorts. For MAD (N = 27), sequential cohorts of male and female participants received 36/100/200 mg JNJ-64264681 once daily for 10 days. JNJ-64264681 exposure (peak concentration; area under the concentration-time curve) was less than dose proportional from 4 mg to 36 mg. Dose-normalized area under the concentration-time curves following the 36 mg and 100 mg doses were generally similar. The mean terminal half-life was 1.6-13.2 hours. With multiple doses, steady state was achieved by day 2. A semimechanistic PK/PD model was developed using the first 5 SAD cohorts' data to predict %BTKO in MAD cohorts. PK/PD model guided dose-escalation, and all participants in the 200/400 mg single-dose cohorts achieved ≥90% BTKO at 4 hours after dosing (peak) with prolonged occupancy. As BTKO data became available from MAD cohorts, it was found that observed BTKO data were consistent with model predictions. JNJ-64264681 showed no safety signals of concern. Overall, safety, tolerability, PK, BTKO, and PK/PD modeling guided the rationale for dose selection for the subsequent first-in-patient lymphoma studies.

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Discovery of JNJ-64264681: A Potent and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase

Cited by 5 publications

References 32 publications

Application of Chiral Piperidine Scaffolds in Drug Design

Application of Chiral Piperidine Scaffolds in Drug Design

Controlling Ibrutinib’s Conformations about Its Heterobiaryl Axis to Increase BTK Selectivity

A Phase 1 First‐in‐Human Pharmacokinetic and Pharmacodynamic Study of JNJ‐64264681, a Covalent Inhibitor of Bruton's Tyrosine Kinase

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