| Contributors |
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ix | |
| Preface |
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xi | |
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1 Kinetic mechanisms of covalent inhibition |
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1 | (32) |
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1 | (1) |
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2 | (5) |
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3 Data analysis techniques |
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7 | (12) |
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4 Experimental techniques |
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19 | (5) |
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24 | (9) |
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25 | (1) |
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25 | (8) |
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2 Covalent drugs in development for immune-mediated diseases |
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33 | (42) |
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33 | (2) |
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2 Developing covalent kinase inhibitors for immune-mediated diseases |
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35 | (10) |
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3 Evobrutinib--Multiple sclerosis |
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45 | (5) |
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4 BMS-986195 (Branebrutinib): Preclinical safety and efficacy determination to Ph 1 clinical trials |
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50 | (11) |
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5 LOU064 (Remibrutinib): Preclinical safety and efficacy determination to Ph I clinical trials |
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61 | (6) |
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6 PRN1008 in clinical trials |
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67 | (4) |
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71 | (4) |
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72 | (3) |
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3 Chemistry perspectives of reversible covalent drugs |
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75 | (20) |
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75 | (1) |
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2 Prominent examples of RCDs |
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76 | (4) |
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3 Thermodynamic considerations of RCD design |
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80 | (4) |
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4 Kinetic considerations of RCD design |
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84 | (4) |
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5 Challenges and future perspectives |
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88 | (4) |
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92 | (3) |
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92 | (1) |
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92 | (3) |
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4 Design of next-generation covalent inhibitors: Targeting residues beyond cysteine |
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95 | (40) |
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95 | (1) |
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2 Lysine (and N-terminal amine) |
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96 | (7) |
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103 | (8) |
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111 | (5) |
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116 | (2) |
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6 Others (glutamate, aspartate, methionine) |
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118 | (3) |
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7 Conclusions and future opportunities |
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121 | (14) |
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124 | (1) |
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124 | (11) |
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5 Boron and covalent inhibition |
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135 | (68) |
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1 General design principles--Covalent and non-covalent approaches |
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137 | (2) |
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139 | (39) |
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3 Designing for pharmacokinetic and chemical stability |
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178 | (9) |
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187 | (6) |
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5 Opportunities and inspiration from nature |
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193 | (1) |
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194 | (9) |
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194 | (9) |
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6 Measuring and predicting warhead and residue reactivity |
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203 | (26) |
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203 | (1) |
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2 Physical parameters of covalent inhibition |
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204 | (4) |
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3 Predicting warhead reactivity |
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208 | (12) |
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4 Limitations of descriptor-based analysis |
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220 | (1) |
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5 Conclusions and future directions |
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221 | (8) |
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222 | (7) |
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7 Computational support of structure-based targeted covalent inhibitor design |
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229 | (14) |
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229 | (3) |
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232 | (1) |
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3 Computational support of structure-based TCI design |
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233 | (5) |
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238 | (5) |
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239 | (4) |
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8 Covalent fragment screening |
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243 | (24) |
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1 Covalent fragment screening |
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244 | (3) |
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2 Covalent fragment libraries |
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247 | (6) |
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3 Commercial covalent fragment libraries |
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253 | (2) |
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4 Notable successful applications of covalent fragment screening |
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255 | (4) |
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5 Chemoproteomic fragment screens |
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259 | (1) |
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6 Conclusions and outlook |
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260 | (7) |
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262 | (5) |
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9 The future of covalent inhibition |
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267 | (12) |
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1 New electrophilic warheads |
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268 | (1) |
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2 Covalent fragment approaches |
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269 | (2) |
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3 Covalent PROTAC methods |
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271 | (1) |
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4 Covalent proteomics and phenotypic approaches |
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272 | (2) |
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274 | (5) |
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279 | (1) |
| References |
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279 | |
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